How the Extracellular Matrix Drives Rheumatoid Arthritis?

Page 1 of 25

Review

The pro-inflammatory niche: how the extracellular matrix drives rheumatoid arthritis?

Cellular & Molecular Mechanisms M Ruhmann, KS Midwood*

Abstract Introduction body of evidence supporting a major Introduction The extracellular matrix (ECM) is a role for these proteins in driving the The extracellular matrix is a complex organization of secreted mol- response to tissue injury1,2. The aim of complex, three-dimensional network ecules. The major constitutive compo- this review is to discuss how the ECM of secreted molecules that provides nents of the ECM include collagens, drives persistent inflammation upon structural support to tissues and elastin, fibronectin, hyaluronic acid tissue damage to the joint in rheuma- environmental cues to the cells and proteoglycans. Together these toid arthritis (RA). within. One particular subset of molecules form a network that pro- matrix molecules is specifically ex- vides structural support for tissues Discussion pressed upon tissue damage. These and delivers environmental signals The authors have referenced some molecules contribute to effective that regulate cell behaviour. However, of their own studies in this re- tissue repair by orchestrating the there exists a unique subset of ECM view. These referenced studies have behaviour of cells that mediate this molecules that are not constitutively been conducted in accordance with process, and once the repair is com- expressed. Found at high levels dur- the Declaration of Helsinki (1964), plete, the expression of this matrix is ing development, but absent from and the protocols of these studies down-regulated. Here, we focus on most healthy adult tissues, these pro- have been approved by the relevant the recent data that highlights a direct teins are specifically induced at sites ethics committees related to the role for injury-induced matrix mol- of tissue injury. These molecules have institution in which they were per- ecules in driving inflammation upon been termed ‘matricellular proteins’ formed. All human subjects, in these tissue damage and propose that and include the CCN family (CCN1-6), referenced studies, gave informed this matrix creates a specific micro galectins (Gal), fibulins, osteopontin consent to participate in these environment or ‘pro-inflammatory (OPN), periostin, secreted protein studies. niche’ that is permissive for local- acidic and rich in cysteine (SPARC), ized inflammation during repair. We small leucine rich proteoglycans Control of tissue repair by the ECM also examine the evidence indicating (SLPRs), tenascin-C (TNC) and throm- Tissue repair is a dynamic and that this niche exists, and persists, bospondins-1 and -2 (TSP-1/2). De- highly organized process that can be in the damaged joint of rheumatoid spite their structural diversity, these divided into three distinct but over- arthritis patients. Finally, we as- molecules possess a number of defin- lapping phases: inflammation, new sess the data which demonstrate ing common features in addition to tissue formation and tissue remodel- that these matrix molecules ac- their distinct pattern of expression. ling. During wound healing, a tempo- tively contribute to maintaining They are key orchestrators of cell rary matrix is deposited that acts as chronic inflammation during disease behaviour; this is mediated by their a template for repair and is eventu- progression. multimodular structure, which con- ally replaced by new structural ECM Conclusion fers the ability to interact with a large components, including collagen and Together these findings imply that number of diverse binding partners fibronectin, to restore the physical in- targeting the pro-inflammatory niche such as cell surface receptors, other tegrity of the tissue and re-establish in the joint may provide a novel ECM molecules, hormones, growth cellular homeostasis. Matricellular treatment strategy for rheumatoid factors and cytokines. Moreover, they proteins are specifically up-regulated arthritis. exert control over a wide range of cell at distinct points during wound heal- functions in a highly context- and cell ing. Their expression is transient; type-specific manner. Finally, although mRNA synthesis is down-regulated highly expressed during develop- and protein cleared from the site be- * Corresponding author ment, mice with targeted disruptions fore the end of tissue repair. Their Email: [email protected] in these genes exhibit grossly normal contribution to effective tissue repair Kennedy Institute of Rheumatology, Nuffield phenotypes until subjected to tissue has been reviewed in an issue dedi- Department of Orthopaedic Rheumatology and 3 Musculoskeletal Sciences, Oxford University, injury, whereupon they exhibit ab- cated to matricellular proteins , and Aspenlea Road, No. 65, London, W6 8LH, UK. normal tissue repair. There is a large Figure 1 summarizes the expression

Licensee OA Publishing London 2013. Creative Commons Attribution License (CC-BY)

For citation purposes: Ruhmann M, Midwood KS. The pro-inflammatory niche: how the extracellular matrix drives

rheumatoid arthritis? OA Arthritis 2013 Mar 02;1(1):6. none declared. declared in the article . Conflict of interests: interests: Competing the final manuscript. as well read and approved design, and preparation of the manuscript, the conception, to All authors contributed rules of disclosure. ethical Ethics (AME) for Medical the Association All authors abide by Page 2 of 25

Review

Figure 1: The role of the ECM in tissue repair. The first response to injury includes the formation of a blood clot consisting of platelets and a fibrin/fibronectin-rich provisional matrix to prevent blood loss. Soluble cytokine and growth factors released by aggregated platelets promote the infiltration of a range of cell types into the provisional matrix. Neutrophils and macrophages cleanse the wound by removing debris, and re-epithelialization is promoted through the migration and proliferation of keratinocytes. The provisional matrix is replaced by granulation tissue which comprises new blood vessels, macrophages and activated fibroblasts that secrete type III collagen and fibronectin. Some fibroblasts differentiate into myofibroblasts that contract and bring the edges of the wound together. The final phase of wound healing starts about two weeks after tissue injury and lasts for at least one year. Most macrophages, fibroblasts and endothelial cells undergo apoptosis. Type III collagen is replaced by type I collagen that is reorganized and cross-linked to produce scar tissue with a higher tensile strength. Matricellular proteins are induced at distinct points after tissue injury and mediate effective tissue deposition and remodelling during repair283. Red arrows represent inhibition, and green arrows indicate stimulation, of the delineated event. References are shown in brackets. and function of some of the key also play a role in the initial inflam- injury. The expression of cytokines, matricelluar proteins during tissue matory response to tissue injury4–42. chemokines, proteases and growth injury. Whilst their importance in factors by these cells orchestrates driving adhesion, migration, matrix The ECM supports immune cells subsequent phases of tissue repair deposition, angiogenesis, prolifera- and drives inflammation during including tissue debris clearance and tion and survival in stromal cells such tissue repair pathogen resorption, recruitment as fibroblasts, endothelial cells and The inflammatory response following and activation of further cells and keratinocytes during tissue forma- tissue damage is characterized by in- cell types, and new tissue formation tion and remodelling has long been filtration of a range of immune cells, and remodelling. It is becoming established, in the last decade it has including neutrophils, macrophages increasingly apparent that matricel- emerged that matricellular proteins and lymphocytes, to the site of lular proteins have a direct impact

Licensee OA Publishing London 2013. Creative Commons Attribution License (CC-BY)

For citation purposes: Ruhmann M, Midwood KS. The pro-inflammatory niche: how the extracellular matrix drives

Review

on inflammation in the early stages induce cytokine, chemokine and half-life, these molecules are large of tissue repair. This is discussed protease expression using distinct proteins that accumulate as part of a below and summarized in Table 1. mechanisms: activation of toll-like dense matrix specifically assembled A number of matricellular mol- receptor 4 (TLR4) in primary human at the site of injury. This physical ecules have been shown to support macrophages and synovial fibro- presence enables them to provide the adhesion of different types of blasts, and murine neutrophils47,48 a scaffold for immune cell adhesion immune cells, others to promote im- and activation of α9 integrins in and migration as well as forming a mune cell migration, whilst some primary murine arthritic synovial reservoir for soluble mediators of enhance immune cell survival and fibroblasts, macrophages and den- inflammation, but these molecules proliferation. Together, these data dritic cells43,44. It achieves this via also directly interact with cells to suggest that matricellular proteins ligation of integrins using its third stimulate inflammatory behaviour. provide an environment that allows fibronectin type III like domain This creation of a ‘pro-inflammatory immune cells to infiltrate and thrive (FNIII)43,44 and activation of TLR4 niche’ by matrix molecules induced at the site of tissue injury. These data via its fibrinogen-like globe (FBG)47. upon injury may shed new light on also reveal that matricellular mole- In addition to driving de novo syn- how we perceive the role of the ECM cules have both distinct and overlap- thesis of pro-inflammatory media- during tissue repair. ping functions during inflammation. tors, matricellular proteins can also For example, mice deficient in TNC bind directly to these mediators and A pro-inflammatory niche in the or TSP-1 both exhibit lower numbers modulate their activity. For example, RA joint of macrophages in corneal or dermal TNC interacts with a range of growth In addition to their transient expres- wounds, respectively, indicating that factors including FGF, PDGF and sion at sites of tissue repair, matricel- these proteins promote macrophage TGFβ via its FNIII 4–5 repeats49 and lular proteins are expressed at high infiltration or survival during wound TSP-1 activates latent TGFβ50,51. As levels in diseases characterized by healing32,38. In contrast, macrophage such, these proteins may further chronic inflammation and extensive infiltration into skin incisions is not potentiate inflammation by acting tissue destruction. This includes au- impaired in OPN-deficient mice com- as a reservoir for soluble mediators toimmune diseases such as RA. The pared to wild-type mice; however, the enabling their presentation in an hallmark of RA is prolonged immune level of tissue debridement is signifi- active form at high local concentra- cell migration into the joint and syno- cantly reduced, indicating that OPN tions to immune cells. vial hyperplasia. Persistent synthesis plays a role in macrophage activation The pro-inflammatory activity of pro-inflammatory mediators by during cutaneous wound healing25. of matricellular proteins is in part these infiltrating immune cells and Indeed, many matricellular pro- regulated by their tightly controlled resident fibroblasts causes chronic teins have also been shown to di- expression during tissue repair, but synovial inflammation and the pro- rectly interact with immune cells to can also be controlled by fellow duction of an invasive pannus medi- drive a pro-inflammatory phenotype. members of the family. For exam- ates destruction of healthy articular The mechanisms by which these ple, whilst a pro-inflammatory role cartilage and bone. Matricellular pro- functions are mediated are proving has been reported for the majority teins are predominantly absent from complex. For example, both OPN and of these molecules, TSP-2 appears normal joints, however, SPARC was TNC induce the expression of pro- more prone to inhibiting inflamma- reported at high levels in RA synovial inflammatory mediators in immune tory processes; it prevents T-cell mi- tissue and fluid as early as 1996134, cells. OPN has been shown to me- gration and leukocyte rolling as well and TNC expression has long been diate these effects via activation of as suppressing pro-inflammatory cy- observed in the RA synovium, lo- a number of cell surface receptors; tokine synthesis and promoting the calized to areas of inflammation it induces the synthesis of specific activation of regulatory T cells52–54. and fibrosis, specifically below the cytokines, chemokines and prote- Thus, the complex interplay between synovial lining, in the invading pan- ases in primary murine arthritic these molecules during tissue repair nus, in fibrin-rich deposits and synovial fibroblasts, macrophages appears to control both the induction around blood vessels135–138. More and dendritic cells via activation of and resolution of inflammation. recently, an up-regulation in the α9integrins43,44, it induces cytokine Together, these data reveal ma- expression of other matricellular synthesis in murine macrophage cell tricellular proteins as rather unique proteins has been reported in the RA lines via activation of β3 integrins45 pro-inflammatory stimuli. Un- joint (Table 2). For example, OPN is and it stimulates CD4 T-cell mi- like most inflammatory mediators, found in the synovium and the invad- gration and cytokine synthesis via such as cytokines, which comprise ing pannus139, demonstrating a simi- activation of CD4445,46. TNC can also small, soluble molecules of a limited lar pattern of expression to Gal-3140.

Licensee OA Publishing London 2013. Creative Commons Attribution License (CC-BY)

For citation purposes: Ruhmann M, Midwood KS. The pro-inflammatory niche: how the extracellular matrix drives

Review

Table 1. Pro-inflammatory functions of matricellular proteins. Protein Function References

CCN1 Promotes macrophage and monocyte adhesion 55, 56

Promotes adhesion and migration of circulating CD34+ progenitor cells 57

Promotes migration of monocytes, macrophages, T cells, B cells, natural killer (NK) cells 58–60

Promotes dendritic cell (DC) growth 61

Activates pro-inflammatory genes in macrophages and CD34+ progenitor cells 55, 57

Promotes CCL2 expression in osteoblastic cells 62

CCN2 Promotes monocyte adhesion 56

Promotes immune cell migration including monocytes, macrophages and T-cells 63, 64

Promotes expression of pro-inflammatory cytokines and chemokines in tubulo-epithelial cells, 64–68 mesangial cells, rat pancreatic stellate cells and cardiomyocytes

Gal-1 Inhibits rolling and adhesion of neutrophils 69

Inhibits T-cell adhesion and pro-inflammatory cytokine production in T-cells 70

Promotes DC activation and migration 71, 72

Induces T-cell apoptosis 73, 74

Promotes differentiation of tolerogenic DCs 75

Promotes Th2 polarization 76–78

Promotes immunoglobulin production during plasma cell differentiation 79

Promotes respiratory burst in neutrophils 80

Promotes Treg activity 81, 82

Inhibits phagocytosis and antigen presentation in monocytes and macrophages 83

Gal-3 Chemoattractant for monocytes and macrophages 84

Promotes DC migration 85

Induces T-cell apoptosis 86, 87

Promotes release of inflammatory mediators in mast cells 88

Promotes IL-2 production and Ca2+ uptake in Jurkat T-cells 89, 90

Inhibits production of pro-inflammatory cytokines in macrophages 91

Promotes respiratory burst in neutrophils 92, 93

Promotes macrophage phagocytosis 94, 95

Licensee OA Publishing London 2013. Creative Commons Attribution License (CC-BY)

For citation purposes: Ruhmann M, Midwood KS. The pro-inflammatory niche: how the extracellular matrix drives

Review

Table 1. Continued. Protein Function References

Promotes alternative macrophage activation 96

Promotes DC-mediated T-cell priming 97

OPN Promotes DC migration, activation, IL-12 and TNFα production and Th1 polarization 98

Promotes Langerhans cell and DC migration through CD44 and αvb3 integrins 99

Promotes macrophage migration, survival and differentiation 100–103

45, 104, Promotes IL-12 and TNFα production in macrophages via activation of α β integrin v 3 103

Inhibits IL-10 production in macrophages via activation of CD44 104

Promotes TLR9-dependent IFNα production in pDCs 105

Promotes IL-17,IFNγ(via β3 integrins) and IL-10 (via CD44) in CD4 T-cells 46

Promotes cytokine production in macrophages and synovial fibroblasts via α9 integrins 43

SPARC Inhibits DC migration and T-cell priming 106

Promotes follicular DC networking towards Th17 responses 107

TNC Promotes monocyte adhesion 108

Promotes macrophage migration 32, 35

Inhibits monocyte/macrophage migration 109

Inhibits chemotaxis of monocytes and polymorphonuclear leukocytes 110

Inhibits proliferation of activated peripheral blood T lymphocytes 111–113

Promotes pro-inflammatory cytokine production in macrophages and synovial fibroblasts via 47 activation of TLR4 Promotes pro-inflammatory cytokine production in DCs and IL-17 production in DC-CD4 T-cell 114 co-cultures Promotes pro-inflammatory cytokine production in macrophages via regulation of microRNA-155 115 expression Promotes pro-inflammatory mediator production in human and bovine chondrocytes via activation 116 of TLR4

Promotes TLR4-dependent differentiation of macrophages into foam cells 117

Promotes MMP9 expression in neutrophils via activation of TLR4 48

Promotes pro-inflammatory cytokine production in macrophages and synovial fibroblasts via 43 activation of α9 integrins

Licensee OA Publishing London 2013. Creative Commons Attribution License (CC-BY)

For citation purposes: Ruhmann M, Midwood KS. The pro-inflammatory niche: how the extracellular matrix drives

Review

Table 1. Continued. Protein Function References

TSP-1 Promotes activated CD4 T-cell adhesion via α4 β1 and α5β1 integrins 118

Promotes neutrophil and monocyte chemotaxis 119, 120

Promotes activation and expansion of CD4 T-cells via CD36/CD47 121

Promotes apoptosis in T-cells, monocytes and DCs 122

Promotes Treg cell differentiation via CD47 123

Regulates cytokine production in monocytes via CD36 124

Inhibits cytokine production in monocytes and DCs via CD47 125–127

Activates latent TGFβ1 50, 51

Drives Th17 responses 51

Promotes macrophage phagocytosis of apoptotic cells via CD36 128, 129

Promotes allosensitization capacity of antigen-presenting cells 130

Promotes DC phagocytic and tolerizing states 131

Inhibits TCR-mediated T-cell activation 132

TSP-2 Inhibits leukocyte rolling during wound healing 133

Inhibits TGFβ activation and T-cell and antigen-presenting cell migration during experimental 52 glomerulonephritis

Inhibits production of pro-inflammatory cytokines and T-cell infiltration during RA 53

Promotes the activation of Tregs 54

However, both exhibit a distinct be interesting to examine if other implying that they possess a role in pattern to Gal-1, which is detected in matricellular proteins are formed innate immune responses in RA. Fur- the RA synovium but excluded from by immune cells and to compare the thermore, these three molecules may the invading pannus140. In consider- form and function of these molecules also impact adaptive immune events ing the source of these matrix mol- from different sources. in the joint; each can drive T-cell po- ecules during RA pathogenesis, the Evidence that matricellular pro- larization down the Th17 lineage in majority of studies examined their teins affect disease progression is vitro44,114,145,147. These are key patho- expression in synovial fibroblasts also emerging (Table 2). For ex- logical cell types that promote tissue and found out that these cells synthe- ample, CCN1 enhances RA synovial erosion in RA and in vivo studies size large amounts of such matrix. In fibroblast proliferation143 suggesting confirm the contribution of CCN-1, addition, however, immune cells can that it may contribute to synovial TNC and OPN in promoting Th17 cell also supply matricellular molecules hyperplasia. CCN1 and other mol- generation in murine models of ar- to the RA joint; myeloid cells of the ecules, such as TNC and OPN, drive thritic disease 44,114,145. In vivo models RA synovium significantly contrib- the synthesis of pro-inflammatory also reveal further information about ute to TNC synthesis141 and TSP-1 is mediators in isolated synovial fibro- the role of matricellular proteins expressed in RA monocytes142. It will blasts and immune cells43,44,47,114,144–146 in disease pathogenesis. OPN null

Licensee OA Publishing London 2013. Creative Commons Attribution License (CC-BY)

For citation purposes: Ruhmann M, Midwood KS. The pro-inflammatory niche: how the extracellular matrix drives

Review

Table 2. Matricellular proteins in the RA joint. Protein Expression/Function in RA References

CCN1 Expressed by RA synovial fibroblasts 144

Expressed in RA synovial tissue 160

Treatment with simvastatin attenuates CIA severity through reduction of CCN1 expression 144

Treatment with epigallocatechin-3-gallate attenuates CIA severity through reduction 161 of CCN1 expression

Promotes IL-17-mediated proliferation of RA fibroblast-like synoviocytes 143

(In synergy with TNFα) Promotes CCL20 production in RA synovial fibroblasts 144

Promotes IL-6 production and Th17 polarization by RA fibroblast-like synoviocytes 145

Treatment with anti-CCN1 mAb attenuates CIA severity (reduced Th17 response) 145

CCN2 Expression is elevated in RA synovial tissue 156

Enhances M-CSF/RANKL-mediated osteoclast activation in RA 156

Treatment with anti-CCN2 mAb attenuates CIA severity (reduced Th17 response, 155 osteoclastogenesis)

CCN4, 5, 6 WISP2 expression is upregulated in RA synoviocytes 162 (WISP1, 2, 3)

CCN5 Expression is upregulated in RA synovial fibroblasts 162 (WISP2)

CCN6 Expression is upregulated in RA synovial fibroblasts 163

Gal-1 Detected in RA joint (not at sites of synovial invasion) 140

Treatment with Gal-1 attenuates CIA severity through promotion of CD4 T-cell apoptosis 149

Treatment with Gal-1-nanogold complex attenuates CIA severity through promotion of 164 CD4 T-cell apoptosis

Overexpression attenuates CIA severity through promotion of CD4 T-cell death 149, 150

Gal-1 chimeric molecule promotes apoptosis in granulocytes from RA synovial fluid 165

Gal-3 Expression is elevated in RA joint (synovial membrane, synovial fluid, sites of joint destruction) 140

Expression is induced in RA synovial fibroblasts after adhesion to cartilage oligomeric matrix 166 protein

Promotes cytokine and chemokine production in RA synovial fibroblasts 151

Null mice exhibit attenuated AIA (reduced Th17 response) 152

Knockdown (lentiviral vector) decreases CIA severity 150

Licensee OA Publishing London 2013. Creative Commons Attribution License (CC-BY)

For citation purposes: Ruhmann M, Midwood KS. The pro-inflammatory niche: how the extracellular matrix drives

Review

Table 2. Continued. Protein Expression/Function in RA References

Gal-9 Expression is elevated in RA synovial tissue and fluid 167

Treatment with stable Gal-9 attenuates CIA severity by induction of apoptosis of synovial 167 fibroblasts

OPN Expressed in the RA synovial membrane and invading synovium 139

Promotes pro-inflammatory cytokine production in synovial fibroblasts and macrophages via 43 activation of α9 integrins Levels correlate with synovial levels of IL-17 and Th17 cells; OPN promotes CD44/29-mediated 147 Th17 cell differentiation in RA synovium Specifically modified OPN expressed by RA fibroblast-like synoviocytes promotes B cell adhesion 146 and IL-6 production Promotes matrix degradation in RA by stimulating the secretion of collagenase 1 in articular 139 chondrocytes

Treatment with anti-OPN mAb attenuates CIA disease severity 153

Null mice exhibit attenuated mAbs/LPS-mediated arthritis 148

Treatment with mAb against a cryptic site of OPN attenuates severity of CIA 154

A cryptic site of OPN promotes migration of monocytes from arthritic mice 154

SPARC Expression is elevated in RA synovial tissue and fluid 134

137, 138, Expression is elevated in RA synovial tissue, synovial fluid and cartilage and serum from RA TNC 141, 168, patients 169

Intraarticular injection of induces TLR4-dependent joint inflammation, bone and cartilage 47 destruction

Null mice are protected from joint inflammation and bone and cartilage destruction during AIA 47

Null mice exhibit reduced zymosan-induced joint inflammation 47

Expression correlates with pro-inflammatory cytokine expression in RA joint 141

Promotes expression of pro-inflammatory cytokines (including IL-17) in arthritic joints 114 during AIA Promotes pro-inflammatory cytokine production in synovial fibroblasts and macrophages via 43 activation of α9 integrins Induces α9-dependent IL-6 production in DCs and macrophages from mice with CIA and Th17 44 polarization

TSP-1 Expression is elevated in RA monocytes 142

Expressed in in RA synovial tissue 53

Licensee OA Publishing London 2013. Creative Commons Attribution License (CC-BY)

For citation purposes: Ruhmann M, Midwood KS. The pro-inflammatory niche: how the extracellular matrix drives

Review

Table 2. Continued. Protein Expression/Function in RA References Treatment with TSP1-derived peptide decreases severity of peptidoglycan-polysaccharide -induced 157, 158 erosive arthritis in rats

Implant increases joint inflammation in adjuvant-induced arthritis 170

Intraarticular expression reduces CIA severity 159

Promotes activation and clonal expansion of autoreactive synovial T cells 121

TSP-2 Expressed in RA synovial tissue 53

Overexpression in RA synovial fibroblasts decreases angiogenesis and inflammation in a human 53 RA synovium-SCID mouse chimera mice exhibit attenuated antibody- of studies show that treatment with ment in the RA joint, first proposed mediated arthritis148, supporting in anti-OPN antibodies attenuates CIA by Kanayama et al. in 200943, sug- vitro data that establish this protein disease severity153,154. Anti-CCN1 an- gests that the pro-inflammatory niche as a pro-inflammatory molecule. tibodies attenuate disease progres- that is designed to help tissue repair, Intraarticular injection of TNC drives sion in CIA by reducing Th17 cell if not properly regulated, can cause a synovial inflammation and joint frequencies145. Anti-CCN2 monoclo- perpetual cycle of inflammation and erosion in a TLR4 dependent man- nal antibodies reduce CIA disease se- tissue damage. This drives an increas- ner. Moreover, whilst joint inflam- verity by reducing osteoclastogeneis ing accumulation of matricellular mation can be initiated in TNC null in inflamed joints155, consistent with molecules in the joint as disease pro- mice, these mice are protected from in vitro data showing that CCN2 gresses causing further, non-resolving prolonged erosive joint destruction, enhances osteoclast activation156. Ex- inflammation. These data also raise implying that TNC is required for dis- ogenous administration of members the interesting possibility that block- ease chronicity47. The different dis- of the thrombospondin family dur- ade of matricellular protein function tribution of galectin family members ing murine models of joint disease or expression may provide a novel in the joints of RA patients implies also affects distinct processes dur- means to reduce inflammation in RA. that they may play distinct roles in ing joint inflammation. Intraperito- the RA synovium. Indeed, Gal-1 has neally administered TSP-1 peptides The ECM derived niche: lessons from been shown to promote the apoptisis decreased the severity of peptidogly- the bone marrow and cancer of T-cells in vitro and intraperitoneal can-polysaccharide-induced erosive This idea that the ECM creates spe- administration of exogenous Gal-1 arthritis in rats157,158 and intraarticu- cialized areas to support specific or intraarticular overexpression me- lar adenovirus-mediated expression cell types and locally modulate cell diated by lentiviral gene transfer of TSP-1 reduced CIA severity159. behaviour is not at all new. Stem during collagen induced arthritis Intraperitoneal injection of TSP- cells, characterized by their capacity (CIA) in mice attenuates disease se- 2-expressing fibroblasts reduced for self-renewal and their ability to verity by enhancing T-cell death149,150. inflammation in vivo as well as ame- differentiate into different cell types, In contrast, Gal-3 promotes cytokine liorating angiogenesis in human RA are found in specific microenviron- production in RA synovial fibro- synovium-severe combined immuno- ments termed ‘niches’. This concept blasts151. Genetic deletion of Gal-3 deficiency (SCID) mouse chimeras53. was first proposed by Schofield in or lentiviral-mediated knockdown of Together, these data indicate that a 1978 to describe the compartment its expression in the joint attenuates complex mixture of matrix molecules of the bone marrow where haema- CIA severity150,152. Finally, adminis- is deposited upon injury to the RA topoietic stem cells (HSCs) reside171. tration of neutralizing monoclonal joint, which creates a niche that sup- The haematopoietic niche contains antibodies that recognize individual ports immune cells and synovial fi- a range of cell types of different matricellular proteins has demon- broblasts, and which is permissive for lineages, as well as specific ECM strated positive therapeutic effects pro-inflammatory processes to occur. molecules and soluble factors that in murine models of RA. A number This idea of a specific microenviron- together modulate HSC behaviour172.

Licensee OA Publishing London 2013. Creative Commons Attribution License (CC-BY)

For citation purposes: Ruhmann M, Midwood KS. The pro-inflammatory niche: how the extracellular matrix drives

Review

Niches have also been proposed to metastasis is a multistep process, in- of a metastatic niche promotes the play an important role in cancer devel- volving the dissemination of cancer growth of metastases176. Both the CSC opment, both in the primary tumour, as cells from the primary tumour site and the metastatic niches contain a well as at metastatic sites. Some stud- to distant tissues. The ‘seed and soil’ range of stromal as well as immune ies indicate that tumours contain low hypothesis by Paget175 proposes that cells, ECM components, cytokines and numbers of cancer stem cells (CSCs), metastatic cells (‘seeds’) require a per- growth factors177. characterized by their capacity to self- missive microenvironment (‘soil’) for Increasing evidence indicates that renew and initiate new tumours173. the generation of metastases at second- matricellular proteins are crucial com- Similar to HSCs, these cells inhabit a ary sites. In the metastatic niche model, ponents of haematopoietic niches, specialized microenvironment, the the formation of a pre-metastatic niche where they regulate key aspects of CSC niche, which controls their main- is required for tumour cell engraft- stem cell behaviour (Table 3). For ex- tenance and differentiation174. Tumour ment, and the subsequent formation ample, OPN-deficient mice exhibit

Table 3. Matricellular proteins in the haematopoietic and metastatic niches. Protein Expression/Function References

CCN1

Haematopoietic Expressed by MSCs 189 niche

Promotes osteoblast differentiation of MSCs 190

Is a chemo attractant for multipotent MSCs 191

Promotes MSC proliferation 192

Metastatic niche Expressed in a range of tumours 193

Promotes breast cancer cell migrationin vitro 194

Overexpression promotes tumour growth and vascularization in vivo 195

Overexpression promotes glioma cell growth in vitro and in vivo 196

Overexpression inhibits melanoma tumour growth and metastasis 197

Inhibits hepatocellular carcinoma cell proliferation and invasion 198

CCN2

Haematopoietic Expressed in the bone marrow 199 niche

Expressed by MSCs 189

Promotes MSC differentiation into fibroblasts 200, 201

Promotes osteogenic differentiation of MSCs 202

Promotes bone marrow stromal cell attachment 203

Promotes osteogenesis in vivo 204

Licensee OA Publishing London 2013. Creative Commons Attribution License (CC-BY)

For citation purposes: Ruhmann M, Midwood KS. The pro-inflammatory niche: how the extracellular matrix drives

Review

Table 3. Continued. Protein Expression/Function References

Metastatic niche Expressed in a range of tumours 193

Inhibits lung cancer metastasis via promotion of cell death 205

Knockdown inhibits pancreatic tumour growth in vitro and in vivo 206

Inhibition reduces pancreatic cancer tumour growth and metastasis in vivo 207 Gal-1

Haematopoietic Expressed by stromal and haematopoietic cells in the bone marrow 183 niche

Expressed by MSCs 208

Gal-1+ stromal cells in the bone marrow constitute a niche for pre-BII cells 183, 209

Promotes pre-BII cell proliferation and differentiation 209

Regulates growth and death of premature haematopoietic cells 210

Regulates proliferation and differentiation of bone marrow stromal cells 211

Metastatic niche Expressed in a range of tumours 212

Knockdown inhibits glioma cell growth 213

Promotes tumour growth and metastasis in vivo via increasing T cell apoptosis 214

Knockdown inhibits tumour growth and metastasis in vivo 215

Promotes lung cancer cell invasion in vitro and metastasis in vivo 216

Gal-3

Haematopoietic Expressed in myeloid cells, stromal cells and B cells in the bone marrow 217, 218 niche

Suppresses GM-CSF-induced proliferation and gene transcription in bone marrow cells 217

Knockout mice exhibit modified bone marrow histology 219

Promotes differentiation of myeloid progenitor cells 219

Inhibits B cell differentiation into plasma cells in the bone marrow 218

Metastatic niche Expressed in a range of tumours 220

Inhibition inhibits breast cancer cell growth in vitro and in vivo 221

Inhibits B cell lymphoma cell apoptosis 222

Overexpression promotes malignant transformation of thyroid follicular cells 223

Promotes breast carcinoma cell invasion in vitro 224

Licensee OA Publishing London 2013. Creative Commons Attribution License (CC-BY)

For citation purposes: Ruhmann M, Midwood KS. The pro-inflammatory niche: how the extracellular matrix drives

Review

Table 3. Continued. Protein Expression/Function References

OPN

Haematopoietic Expressed in the endosteal region of the bone marrow by osteoblasts 178 niche

Negatively regulates stem cell numbers in the bone marrow 178

Fragments promote stem and progenitor cell migration, retention and release from the 225 bone marrow

Inhibits HSC proliferation in vitro and in vivo 179

Metastatic niche Expressed in a range of tumours 226

Promotes ovarian cancer cell proliferation, migration, invasion and tumour 186 formation Promotes tumour growth and prostate cancer cell proliferation, migration and 187 invasion

Fragment promotes hepatocellular carcinoma cell invasion via CD44 227

Knockdown in renal carcinoma cells increases apoptosis and decreases 228 invasiveness Overexpression promotes fibrosarcoma or pancreatic tumour growth and lung 229 metastasis through inhibition of apoptosis

SPARC

Haematopoietic Knockout mice have no defects in steady state haematopoiesis or haematopoieitic 230 niche recovery after myeloablation

Promotes osteoblast formation, maturation and survival 231

Promotes erythroid colony forming capacity 230, 232

Promotes erythroid cell progenitor differentiation in zebrafish 233

Metastatic niche Expressed in a range of tumours 234

Overexpression reduces breast cancer cell invasion and colony formation in vitro and 235 bone metastasis in vivo

Overexpression promotes glioblastoma invasion in vitro 236

Knockdown abrogates human melanoma cell tumourigenicity in vitro and in vivo 237

Inhibits tumour cell growth in vitro and in vivo 238

Overexpression inhibits tumour growth in vivo 239

Licensee OA Publishing London 2013. Creative Commons Attribution License (CC-BY)

For citation purposes: Ruhmann M, Midwood KS. The pro-inflammatory niche: how the extracellular matrix drives

Review

Table 3. Continued. Protein Expression/Function References

TNC

Haematopoietic 180, 181, Expressed by stromal and endothelial cells in the bone marrow niche 240, 241

Promotes adhesion of haematopoietic cells to stromal cells 181, 182

Promotes the generation of haematopoietic progenitor cells in long term bonemarrow 242 cultures

Promotes the proliferation of haematopoietic stem and progenitor cells in vitro and in vivo 180

Knockout mice exhibit impaired haematopoietic recovery after bone marrow ablation 180

Metastatic niche Expressed in a range of tumours 243

Knockdown reduces breast cancer cell migration, proliferation, tumour growth and lung 244 metastasis

Knockdown reduces survival and outgrowth of lung metastases 188

Promotes the survival of Metastasis-initiating breast cancer cells by EnhancingWnt and 188 Notch signalling

Promotes metastatic colonization 245

Inhibits IFNγ production by tumour-infiltrating lymphocytes 111

Overexpression promotes breast cancer cell invasion and proliferation through up- 246 regulation of MMP expression

Inhibits transmigration of T-lymphocytes in glioblastoma 247

TSP-1

Haematopoietic Expressed by haematopoietic and stromal cells in the bone marrow 248 niche

Inhibits osteogenic differentiation of MSCs through activation of TGFβ 249

Promotes adhesion of haematopoietic progenitor cells 248, 250

Inhibits megakaryocytopoiesis 251

Metastatic niche Expressed in a range of tumours 252

Overexpression inhibits melanoma angiogenesis and lung metastasis in vivo 253

Promotes breast cancer cell migration in vitro and metastasis in vivo 254

Knockdown inhibits prostate tumour growth in vivo 255

Promotes the recruitment of M1 tumour-associated macrophages (TAMs) 256

Inhibits mammary tumour angiogenesis and growth in vivo 257

Licensee OA Publishing London 2013. Creative Commons Attribution License (CC-BY)

For citation purposes: Ruhmann M, Midwood KS. The pro-inflammatory niche: how the extracellular matrix drives

Review

Table 3. Continued. Protein Expression/Function References

TSP-2

Haematopoietic Expressed by MSCs in the bone marrow 208, 258 niche

Expressed by haematopoietic stem and progenitor cells 259

TSP-2 deficiency increases osteoprogenitor cell numbers and proliferation 260, 261

Inhibits MSC proliferation 258

Promotes platelet release from megakaryocytes 262

Promotes adhesion of haematopoietic stem and progenitor cells 259

Metastatic niche Expressed in a range of tumours 263

Overexpression inhibits melanoma invasiveness in vitro and liver metastasis in vivo 264

Deficiency promotes skin carcinoma tumour angiogenesis and decreases tumour cell 265 apoptosis Overexpression inhibits squamous cell carcinoma tumour growth and angiogenesis in 266 vivo

Overexpression inhibits pancreatic cancer cell invasion in vitro 267

Knockdown inhibits invasion of tumour-derived pancreatic stellate cells 268

increased frequencies of stem cells types in vitro186,187 and TNC expression can exert on different cells within in the bone marrow, and OPN was by breast cancer cells promotes their different niches. The answer most shown to inhibit HSC proliferation ability to metastasise into the lungs by likely lies in the precise combination in vitro and in vivo178,179. In contrast, enhancing cancer stem cell fitness188. of proteins that make up the niche TNC-deficient mice have no defects in Throughout this literature, there is together with the cell surface recep- steady state haematopoiesis; however, a strong emphasis on matricellular tor repertoire of the interacting cells haematopoietic recovery after bone proteins promoting stem and can- to enable a context-specific response. marrow ablation is impaired in these cer cell survival, differentiation and A number of studies have gone mice180. TNC was shown to promote proliferation. It will be interesting to into addressing these issues. Pri- the adhesion of HSCs to stromal cells see whether these molecules, which mary tumours do not metastasize to and to promote the proliferation of from their matrix in the RA joint all tissues, and indeed tumours of hematopoietic stem and progenitor can promote inflammation, also af- distinct types often migrate to dif- cells181,182. Gal-1-expressing stromal fect inflammation within the tumour ferent secondary sites. This suggests cells were identified as a component stroma. Whilst inflammation is now that a specific type of soil is required for a pre-BII cell-specific niche in the widely recognized as a key feature by specific tumours seeds176. More- bone marrow183. Matricellular protein of cancer disease progression, in- over, metastasis of the same tumour expression in metastatic niches has flammation within the homeostatic type to different secondary sites is also been shown to regulate different environment of the bone marrow, driven by very different molecular aspects of tumour progression and however, would be extremely detri- mechanisms. Genes that are spe- metastasis184,185 (Table 3). For example, mental. Thus, the question arises as cifically associated with breast can- OPN promotes the proliferation, migra- to what dictates the particular effects cer cells that metastasize to the tion and invasion of various cancer cell that the same matricellular protein lungs are largely distinct from the

Licensee OA Publishing London 2013. Creative Commons Attribution License (CC-BY)

For citation purposes: Ruhmann M, Midwood KS. The pro-inflammatory niche: how the extracellular matrix drives

Review

gene-expression signature of breast osteal bone surfaces and proposed cells and resident fibroblasts cancer cells that exhibit high poten- to promote HSC quiescence, and the (Figure 2). Analogous to the metastatic tial to metastasize to the brain or to vascular niche, localized at the sur- niche ‘seed and soil’ paradigm, where bone269–271. Amongst these gene sets, faces of sinusoidal blood vessels and the extracellular environment is es- for example TNC was enriched in proposed to promote HSC prolifera- sential for supporting tumour cell sur- those breast cancer cells that spread tion and differentiation272. It will be vival176, we propose that the creation to the lungs, but not to other sites. of great interest to examine the com- of an extracellular niche within the This implies that there is not one position of the ECM in each of these synovium helps to sustain chronic in- type of unifying ECM environment locations. flammation. Synovial fibroblasts from that comprises a metastatic niche RA joints autonomously induce joint but there exists specific ECM signa- Conclusion disease upon systemic injection into tures for specific cancers. Recently, Here we describe a model for RA dis- mice, but do not cause inflammation two distinct types of haematopoietic ease pathogenesis in which the syno- in any other tissue273, indicating that niche have also been defined: the vial environment is key to determining factors endogenous to the synovium osteoblastic niche, localized at end- the behaviour of infiltrating immune support site-specific disease induction.

Figure 2: Model of how the pro-inflammatory niche drives sustained inflammation in RA. Many ECM molecules that are induced in response to tissue damage are found at high levels in the RA joint. Here we propose that they form a pro-inflammatory niche which supports immune cell infiltration, and is permissive for both infiltrating immune cells and tissue resident cells to proliferate and thrive. By virtue of their multimodular domain structures, ECM molecules also interact with a variety of cell surface receptors in a number of types to actively regulate many different aspects of inflammatory cell behaviour. Finally, this ECM also integrates signals from soluble mediators by acting as a reservoir for cytokines, chemokines and growth factors. Lack of effective control of the expression of these matrix molecules, coupled with or caused by, progressive tissue damage serves to create an environment that contributes to a prolonged immune response in the RA joint. Development of agents that block the pro-inflammatory action of this niche, either alone or coupled to established anti-inflammatory agents, may reveal new strategies to locally dampen chronic inflammation in the RA joint without globally ablating the immune response.

Licensee OA Publishing London 2013. Creative Commons Attribution License (CC-BY)

For citation purposes: Ruhmann M, Midwood KS. The pro-inflammatory niche: how the extracellular matrix drives

Review

Targeting the metastatic niche, as well we target one or all matricellular mol- 2. Roberts DD. Emerging functions of as the metastasizing cell, is proving ecules, aim to block single or common matricellular proteins. Cell Mol Life Sci. essential for effective prevention of pro-inflammatory pathways, must be 2011 Oct;68(19):3133–6. tumor progression184,188,274,275. Identifi- addressed to fully understand how this 3. Bornstein P. Matricellular proteins: an overview. J Cell Commun Signal. 2009 cation of a pro-inflammatory niche in complex matrix functions in RA and if Dec;3(3–4):163–5. the joint could also provide an entirely we wish to use matricellular protein 4. Jun JI, Lau LF. Taking aim at the novel means of treating RA. The ex- expression in the joint for anything other extracellular matrix: CCN proteins as pression of injury specific ECM mole- than a sophisticated delivery system. emerging therapeutic targets. Nat Rev cules not found in healthy tissues may Drug Discov. 2011 Dec;10(12):945–63. serve as a postcode to direct delivery Competing interests 5. Kim KH, Chen CC, Monzon RI, Lau of anti-inflammatory agents to the in- KM and MR have filed patents LF. The Matricellular Protein CCN1 flamed synovium. Combination of this around targeting the pro-inflamma- Promotes Regression of Liver Fibrosis approach with agents that prevent tory function of tenascin-C. KM is a through Induction of Cellular Senescence in Hepatic Myofibroblasts. Mol Cell Biol. ECM-mediated inflammation may pro- founder and director of Nascient Ltd. 2013 May;33(10):2078–90. vide a powerful, tissue-specific strat- 6. Chen CC, Mo FE, Lau LF. The egy for RA treatment. Acknowledgement angiogenic factor Cyr61 activates a Indeed, in the cancer field using TNC KM is supported by a Senior genetic program for wound healing in as a means to deliver cytotoxic agents Research Fellowship from Arthritis human skin fibroblasts. J Biol Chem. to glioma sites has proved an effective Research, UK and MR by a Ph.D. stu- 2001 Dec;276(50):47329–37. means of reducing tumour burden276–81. dentship from The Kennedy Trust. 7. Latinkic BV, Mo FE, Greenspan JA, Expanding on this theme, Schwager Copeland NG, Gilbert DJ, Jenkins NA, et al, in a recent and very elegant study, et al. Promoter function of the angio- Abbreviations genic inducer Cyr61gene in transgenic conjugated monoclonal antibodies AIA, Antigen-induced arthritis; CIA, mice: tissue specificity, inducibility dur- raised against fibronectin EDA, a splice Collagen-induced arthritis; CSC, ing wound healing, and role of the serum variant of this matrix glycoprotein that is Cancer stem cell; DC, Dendritic response element. Endocrinology. 2001 specifically induced during tissue injury cell; ECM, Extracellular matrix; Jun;142(6):2549–57. and found at high levels in RA synovia, FBG, Fibrinogen globe; FGF, 8. Mori T, Kawara S, Shinozaki M, to the anti-inflammatory cytokine IL- Fibroblast growth factor; FNIII, Fi- Hayashi N, Kakinuma T, Igarashi A, et al. Role and interaction of connective tis- 10. These conjugates were systemically bronectin type III domain; Gal, sue growth factor with transforming administered during murine CIA and Galectin; GM-CSF, Granulocyte demonstrated significant inhibition of growth factor-beta in persistent fibrosis: macrophage-colony-stimulating fac- A mouse fibrosis model. J Cell Physiol. the progression of established arthri- tor; HSC, Haematopoietic stem cell; 282 1999 Oct;181(1):153–9. tis . This approach shows that using IFN, Interferon; mAb, Monoclonal 9. Wang JF, Olson ME, Ma L, Brigstock injury-specific ECM to deliver anti-in- antibody; M-CSF, Macrophage-colony DR, Hart DA. Connective tissue growth flammatory agents to the RA joint may stimulating factor; MMP, Matrix factor siRNA modulates mRNA levels be therapeutically useful in treating RA; metalloproteinase; OPN, Osteopontin; for a subset of molecules in normal and fibronectin-EDA- antibody-IL10 conju- PDGF, Platelet-derived growth factor; TGF-beta 1-stimulated porcine skin fibroblasts. Wound Repair Regen. 2004 gates are now being tested in the clinic. RA, Rheumatoid arthritis; RANKL, Mar–Apr;12(2):205–16. However, the data indicating that these Receptor activator of nuclear factor matrix molecules also actively contribute 10. Garrett Q, Khaw PT, Blalock TD, kappa-B ligand; SCID, Severe com- Schultz GS, Grotendorst GR, Daniels to driving inflammation in RA may offer bined immunodeficiency; SLPR, Small JT. Involvement of CTGF in TGF-beta1- additional therapeutic benefit. However, leucine rich proteoglycan; SPARC, stimulation of myofibroblast differen- before this can be achieved there remain Secreted protein acidic and rich in tiation and collagen matrix contraction many intriguing questions to answer. cysteine; TGF, Transforming growth in the presence of mechanical stress. Why do many matricellular molecules factor; Th, T helper; TLR, Toll-like Invest Ophthalmol Vis Sci. 2004 exert the same pro-inflammatory ef- receptor; TNC, Tenascin-c; TNF, Tu- Apr;45(4):1109–16. 11. Frazier K, Williams S, Kothapalli D, fects? Why does a single matricellular mour necrosis factor; Treg, Regula- Klapper H, Grotendorst GR. Stimulation molecule exhibit two or more mecha- tory T cell; TSP, Thrombospondin. nisms for inducing inflammatory cyto- of fibroblast cell growth, matrix production, and granulation tissue forma- kine synthesis? Which molecules (and References tion by connective tissue growth factor. which mechanisms) are key players in 1. Bornstein P, Sage EH. Matricellular J Invest Dermatol. 1996 Sep;107(3): driving inflammation in RA and which proteins: extracellular modulators of 404–11. merely constitute collateral damage? cell function. Curr Opin Cell Biol. 2002 12. Sisco M, Kryger ZB, O’Shaughnessy This question of redundancy, i.e. should Oct;14(5):608–16. KD, Kim PS, Schultz GS, Ding XZ, et al.

Licensee OA Publishing London 2013. Creative Commons Attribution License (CC-BY)

For citation purposes: Ruhmann M, Midwood KS. The pro-inflammatory niche: how the extracellular matrix drives

Review

Antisense inhibition of connective migration after myocardial infarction is myocardial injury. Am J Pathol. 2005 tissue growth factor (CTGF/CCN2) regulated by transient SPARC expression. Jul;167(1):71–80. mRNA limits hypertrophic scar- J Mol Med (Berl). 2006 Mar;84(3):241–52. 34. Midwood KS, Schwarzbauer JE. ring without affecting wound healing 23. Mishima H, Hibino T, Hara H, Mu- Tenascin-C modulates matrix contraction in vivo. Wound Repair Regen. 2008 rakami J, Otori T. SPARC from corneal via focal adhesion kinase- and Rho-me- Sep–Oct;16(5):661–73. epithelial cells modulates collagen con- diated signaling pathways. Mol Biol Cell. 13. Klíma J, Lacina L, Dvoránková B, Her- traction by keratocytes. Invest Ophthal- 2002 Oct;13(10):3601–13. rmann D, Carnwath JW, Niemann H, et al. mol Vis Sci. 1998 Dec;39(13):2547–53. 35. Sumioka T, Fujita N, Kitano A, Okada Differential regulation of galectin expres- 24. Miyazaki K, Okada Y, Yamanaka O, Ki- Y, Saika S. Impaired angiogenic response sion/reactivity during wound healing in tano A, Ikeda K, Kon S, et al. Corneal wound in the cornea of mice lacking tenas- porcine skin and in cultures of epidermal healing in an osteopontin-deficient cin C. Invest Ophthalmol Vis Sci. 2011 cells with functional impact on migra- mouse. Invest Ophthalmol Vis Sci. 2008 Apr;52(5):2462–7. tion. Physiol Res. 2009;58(6):873–84. Apr;49(4):1367–75. 36. Streit M, Velasco P, Riccardi L, 14. Dvořánková B, Szabo P, Lacina L, 25. Liaw L, Birk DE, Ballas CB, Whit- Spencer L, Brown LF, Janes L, et al. Gal P, Uhrova J, Zima T, et al. Human sitt JS, Davidson JM, Hogan BL. Altered Thrombospondin-1 suppresses wound galectins induce conversion of dermal wound healing in mice lacking a healing and granulation tissue formation fibroblasts into myofibroblasts and pro- functional osteopontin gene (spp1). J in the skin of transgenic mice. EMBO J. duction of extracellular matrix: poten- Clin Invest. 1998 Apr;101(7):1468–78. 2000 Jul;19(13):3272–82. tial application in tissue engineering 26. Fujita N, Fujita S, Okada Y, Fujita K, 37. DiPietro LA, Nissen NN, Gamelli RL, and wound repair. Cells Tissues Organs. Kitano A, Yamanaka O, et al. Impaired an- Koch AE, Pyle JM, Polverini PJ. Throm- 2011;194(6):469–80. giogenic response in the corneas of mice bospondin 1 synthesis and function 15. Liu W, Hsu DK, Chen HY, Yang RY, Car- lacking osteopontin. Invest Ophthalmol in wound repair. Am J Pathol. 1996 raway KL 3rd, Isseroff RR, et al. Galectin-3 Vis Sci. 2010 Feb;51(2):790–4. Jun;148(6):1851–60. regulates intracellular trafficking of EGFR 27. Lenga Y, Koh A, Perera AS, Mc- 38. Agah A, Kyriakides TR, Lawler J, through Alix and promotes keratino- Culloch CA, Sodek J, Zohar R. Osteo- Bornstein P. The lack of thrombospon- cyte migration. J Invest Dermatol. 2012 pontin expression is required for din-1 (TSP1) dictates the course of wound Dec;132(12):2828–37. myofibroblast differentiation. Circ Res. healing in double-TSP1/TSP2-null mice. 16. Cao Z, Said N, Amin S, Wu HK, Bruce 2008 Feb;102(3):319–27. Am J Pathol. 2002 Sep;161(3):831–9. A, Garate M, et al. Galectins-3 and -7, but 28. Mori R, Shaw TJ, Martin P. Mo- 39. Uno K, Hayashi H, Kuroki M, not galectin-1, play a role in re-epitheli- lecular mechanisms linking wound in- Uchida H, Yamauchi Y, Kuroki M, alization of wounds. J Biol Chem. 2002 flammation and fibrosis: knockdown et al. Thrombospondin-1 accelerates Nov;277(44):42299–305. of osteopontin leads to rapid repair wound healing of corneal epithelia. 17. Saegusa J, Hsu DK, Liu W, Kuwabara and reduced scarring. J Exp Med. 2008 Biochem Biophys Res Commun. 2004 I, Kuwabara Y, Yu L, et al. Galectin-3 pro- Jan;205(1):43–51. Mar;315(4):928–34. tects keratinocytes from UVB-induced 29. Matsuda A, Yoshiki A, Tagawa 40. Chen Y, Leask A, Abraham DJ, Ken- apoptosis by enhancing AKT activation Y, Matsuda H, Kusakabe M. Corneal nedy L, Shi-Wen X, Denton CP, et al. and suppressing ERK activation. J Invest wound healing in tenascin knockout Thrombospondin 1 is a key mediator Dermatol. 2008 Oct;128(10):2403–11. mouse. Invest Ophthalmol Vis Sci. 1999 of transforming growth factor beta- 18. Henderson NC, Mackinnon AC, May;40(6):1071–80. mediated cell contractility in systemic Farnworth SL, Poirier F, Russo FP, 30. Nakao N, Hiraiwa N, Yoshiki A, Ike sclerosis via a mitogen-activated protein Iredale JP, et al. Galectin-3 regulates F, Kusakabe M. Tenascin-C promotes kinase kinase (MEK)/extracellular sig- myofibroblast activation and hepatic fi- healing of Habu-snake venom-induced nal-regulated kinase (ERK)-dependent brosis. Proc Natl Acad Sci U S A. 2006 glomerulonephritis: studies in knock- mechanism. Fibrogenesis Tissue Repair. Mar;103(13):5060–5. out congenic mice and in culture. Am J 2011 Mar;4(1):9. 19. Bradshaw AD, Reed MJ, Sage EH. Pathol. 1998 May;152(5):1237–45. 41. Kyriakides TR, Tam JW, Bornstein SPARC-null mice exhibit accelerated cu- 31. Forsberg E, Hirsch E, Fröhlich L, P. Accelerated wound healing in mice taneous wound closure. J Histochem Cy- Meyer M, Ekblom P, Aszodi A, et al. with a disruption of the thrombospon- tochem. 2002 Jan;50(1):1–10. Skin wounds and severed nerves heal din 2 gene. J Invest Dermatol. 1999 Mar; 20. Basu A, Kligman LH, Samulewicz SJ, normally in mice lacking tenascin-C. 113(5):782–7. Howe CC. Impaired wound healing in Proc Natl Acad Sci U S A. 1996 42. Maclauchlan S, Skokos EA, Agah mice deficient in a matricellular protein Jun;93(13):6594–9. A, Zeng J, Tian W, Davidson JM, et al. SPARC (osteonectin, BM-40). BMC Cell 32. Sumioka T, Kitano A, Flanders KC, Enhanced angiogenesis and reduced Biol. 2001;2:15. Okada Y, Yamanaka O, Fujita N, et al. Im- contraction in thrombospondin-2-null 21. Strandjord TP, Madtes DK, Weiss DJ, paired cornea wound healing in a tenas- wounds is associated with increased Sage EH. Collagen accumulation is de- cin C-deficient mouse model. Lab Invest. levels of matrix metalloproteinases-2 creased in SPARC-null mice with bleo- 2013 Feb;93(2):207–17. and -9, and soluble VEGF. J Histochem mycin-induced pulmonary fibrosis. Am J 33. Tamaoki M, Imanaka-Yoshida K, Yo- Cytochem. 2009 Apr;57(4):301–13. Physiol. 1999 Sep;277(3 Pt 1):L628–35. koyama K, Nishioka T, Inada H, Hiroe M, 43. Kanayama M, Kurotaki D, Morim- 22. Wu RX, Laser M, Han H, Varadarajulu et al. Tenascin-C regulates recruitment of oto J, Asano T, Matsui Y, Nakayama Y, J, Schuh K, Hallhuber M, et al. Fibroblast myofibroblasts during tissue repair after et al. Alpha9 integrin and its ligands

Licensee OA Publishing London 2013. Creative Commons Attribution License (CC-BY)

For citation purposes: Ruhmann M, Midwood KS. The pro-inflammatory niche: how the extracellular matrix drives

Review

constitute critical joint microenvi- 53. Park YW, Kang YM, Butterfield 62. Kok SH, Hou KL, Hong CY, Wang JS, ronments for development of auto- J, Detmar M, Goronzy JJ, Weyand Liang PC, Chang CC, et al. Simvastatin in- immune arthritis. J Immunol. 2009 CM. Thrombospondin 2 functions as hibits cytokine-stimulated Cyr61 expres- Jun;182(12):8015–25. an endogenous regulator of angio- sion in osteoblastic cells: a therapeutic 44. Kanayama M, Morimoto J, Matsui Y, genesis and inflammation in rheu- benefit for arthritis. Arthritis Rheum. Ikesue M, Danzaki K, Kurotaki D, et al. matoid arthritis. Am J Pathol. 2004 2011 Apr;63(4):1010–20. alpha9beta1 integrin-mediated signaling Dec;165(6):2087–98. 63. Cicha I, Cicha I, Yilmaz A, Klein M, serves as an intrinsic regulator of patho- 54. Papageorgiou AP, Swinnen M, Van- Raithel D, Brigstock DR, Daniel WG, et al. genic Th17 cell generation. J Immunol. houtte D, VandenDriessche T, Chuah Connective tissue growth factor is over- 2011 Dec;187(11):5851–64. M, Lindner D, et al. Thrombospondin-2 expressed in complicated atherosclerotic 45. Weber GF, Zawaideh S, Hikita prevents cardiac injury and dysfunction plaques and induces mononuclear cell S, Kumar VA, Cantor H, Ashkar S. in viral myocarditis through the activa- chemotaxis in vitro. Arterioscler Thromb Phosphorylation-dependent interaction of regulatory T-cells. Cardiovasc Res. Vasc Biol. 2005 May;25(5):1008–13. tion of osteopontin with its recep- 2012 Apr;94(1):115–24. 64. Sánchez-López E, Rayego S, tors regulates macrophage migration 55. Bai T, Chen CC, Lau LF. Matricel- Rodrigues-Díez R, Rodriguez JS, and activation. J Leukoc Biol. 2002 lular protein CCN1 activates a pro- Rodrigues-Díez R, Rodríguez-Vita J, et al. Oct;72(4):752–61. inflammatory genetic program in CTGF promotes inflammatory cell infiltra- 46. Murugaiyan G, Mittal A, Weiner HL. murine macrophages. J Immunol. 2010 tion of the renal interstitium by activat- Increased osteopontin expression in Mar;184(6):3223–32. ing NF-kappaB. J Am Soc Nephrol. 2009 dendritic cells amplifies IL-17 produc- 56. Schober JM, Chen N, Grzeszkie- Jul;20(7):1513–26. tion by CD4+ T cells in experimental wicz TM, Jovanovic I, Emeson EE, Uga- 65. Wu SH, Lu C, Dong L, Chen ZQ. autoimmune encephalomyelitis and rova TP, et al. Identification of integrin Signal transduction involved in CTGF- in multiple sclerosis. J Immunol. 2008 alpha(M)beta(2) as an adhesion re- induced production of chemokines in Dec;181(11):7480–8. ceptor on peripheral blood monocytes mesangial cells. Growth Factors. 2008 47. Midwood K, Sacre S, Piccinini for Cyr61 (CCN1) and connective tis- Aug;26(4):192–200. AM, Inglis J, Trebaul A, Chan E, et al. sue growth factor (CCN2): immedi- 66. Wu SH, Wu XH, Lu C, Dong L, Zhou Tenascin-C is an endogenous activa- ate-early gene products expressed in GP, Chen ZQ. Lipoxin A4 inhibits con- tor of Toll-like receptor 4 that is es- atherosclerotic lesions. Blood. 2002 nective tissue growth factor-induced sential for maintaining inflammation in Jun;99(12):4457–65. production of chemokines in rat mesan- arthritic joint disease. Nat Med. 2009 57. Grote K, Salguero G, Ballmaier M, gial cells. Kidney Int. 2006 Jan;69(2): Jul;15(7):774–80. Dangers M, Drexler H, Schieffer B. The 248–56. 48. Kuriyama N, Duarte S, Hamada T, angiogenic factor CCN1 promotes ad- 67. Karger A, Fitzner B, Brock P, Sparmann Busuttil RW, Coito AJ. Tenascin-C: a hesion and migration of circulating G, Emmrich J, Liebe S, et al. Molecular in- novel mediator of hepatic ischemia and CD34+ progenitor cells: potential role in sights into connective tissue growth factor reperfusion injury. Hepatology. 2011 angiogenesis and endothelial regenera- action in rat pancreatic stellate cells. Cell Dec;54(6):2125–36. tion. Blood. 2007 Aug;110(3):877–85. Signal. 2008 Oct;20(10):1865–72. 49. De Laporte LRJ, Tortelli F, Hub- 58. Rother M, Krohn S, Kania G, Van- 68. Wang X, McLennan SV, Allen TJ, bell JA. Tenascin C Promiscuously Binds houtte D, Eisenreich A, Wang X, et al. Twigg SM. Regulation of pro-inflamma- Growth Factors via Its Fifth Fibronectin Matricellular signaling molecule CCN1 tory and pro-fibrotic factors by CCN2/ Type III-Like Domain. PLoS One. 2013 attenuates experimental autoimmune CTGF in H9c2 cardiomyocytes. J Cell Apr;8(4):e62076. myocarditis by acting as a novel immune Commun Signal. 2010 Mar;4(1):15–23. 50. Crawford SE, Stellmach V, Murphy- cell migration modulator. Circulation. 69. Cooper D, Norling LV, Perretti M. Ullrich JE, Ribeiro SM, Lawler J, Hynes 2010 Dec;122(25):2688–98. Novel insights into the inhibitory effects RO, et al. Thrombospondin-1 is a major 59. Bian Z, Peng Y, You Z, Wang Q, of Galectin-1 on neutrophil recruit- activator of TGF-beta1 in vivo. Cell. 1998 Miao Q, Liu Y, et al. CCN1 expression ment under flow. J Leukoc Biol. 2008 Jun;93(7):1159–70. in hepatocytes contributes to macro- Jun;83(6):1459–66. 51. Yang K, Vega JL, Hadzipasic M, phage infiltration in nonalcoholic fatty 70. Rabinovich GA, Ariel A, Hershkoviz Schatzmann Peron JP, Zhu B, Carrier Y, liver disease in mice. J Lipid Res. 2013 R, Hirabayashi J, Kasai KI, Lider O. Spe- et al. Deficiency of thrombospondin-1 Jan;54(1):44–54. cific inhibition of T-cell adhesion to ex- reduces Th17 differentiation and at- 60. Löbel M, Bauer S, Meisel C, Eisenreich tracellular matrix and proinflammatory tenuates experimental autoimmune A, Kudernatsch R, Tank J, et al. CCN1: a cytokine secretion by human recom- encephalomyelitis. J Autoimmun. 2009 novel inflammation-regulated biphasic binant galectin-1. Immunology. 1999 Mar;32(2):94–103. immune cell migration modulator. Cell May;97(1):100–6. 52. Daniel C, Wagner A, Hohenstein B, Mol Life Sci. 2012 Sep;69(18):3101–13. 71. Fulcher JA, Chang MH, Wang S, Hugo C. Thrombospondin-2 therapy 61. Malik AR, Urbanska M, Gozdz A, Almazan T, Hashimi ST, Eriksson AU, et al. ameliorates experimental glomerulone- Swiech LJ, Nagalski A, Perycz M, et Galectin-1 co-clusters CD43/CD45 on phritis via inhibition of cell proliferation, al. Cyr61, a matricellular protein, is dendritic cells and induces cell activation inflammation, and TGF-beta activation. needed for dendritic arborization of and migration through Syk and protein Am J Physiol Renal Physiol. 2009 hippocampal neurons. J Biol Chem. 2013 kinase C signaling. J Biol Chem. 2009 Nov;297(5):F1299–309. Mar;288(12):8544–59. Sep;284(39):26860–70.

Licensee OA Publishing London 2013. Creative Commons Attribution License (CC-BY)

For citation purposes: Ruhmann M, Midwood KS. The pro-inflammatory niche: how the extracellular matrix drives

Review

72. Fulcher JA, Hashimi ST, Levroney galectin-1 mediates regulatory T cell ac- NADPH-oxidase in exudated but not EL, Pang M, Gurney KB, Baum LG, et al. tivity involving TRPC5 channel activation: peripheral blood neutrophils. Blood. Galectin-1-matured human monocyte- possible role in suppressing experimental 1998 May;91(9):3430–8. derived dendritic cells have enhanced autoimmune encephalomyelitis. J Immu- 93. Yamaoka A, Kuwabara I, Frigeri LG, migration through extracellular matrix. J nol. 2009 Apr;182(7):4036–45. Liu FT. A human lectin, galectin-3 (epsilon Immunol. 2006 Jul;177(1):216–26. 83. Barrionuevo P, Beigier-Bompadre bp/Mac-2), stimulates superoxide pro- 73. Perillo NL, Pace KE, Seilhamer M, Ilarregui JM, Toscano MA, Bianco duction by neutrophils. J Immunol. 1995 JJ, Baum LG. Apoptosis of T cells GA, Isturiz MA, et al. A novel function Apr;154(7):3479–87. mediated by galectin-1. Nature. 1995 for galectin-1 at the crossroad of in- 94. Karlsson A, Christenson K, Mat- Dec;378(6558):736–9. nate and adaptive immunity: galectin-1 lak M, Björstad A, Brown KL, Telemo E, 74. Brandt B, Abou-Eladab EF, Tiedge regulates monocyte/macrophage physi- et al. Galectin-3 functions as an opsonin M, Walzel H. Role of the JNK/c-Jun/ ology through a nonapoptotic ERK- and enhances the macrophage clearance AP-1 signaling pathway in galectin- dependent pathway. J Immunol. 2007 of apoptotic neutrophils. Glycobiology. 1-induced T-cell death. Cell Death Dis. Jan;178(1):436–45. 2009 Jan;19(1):16–20. 2010;1:e23. 84. Sano H, Hsu DK, Yu L, Apgar JR, Ku- 95. Sano H, Hsu DK, Apgar JR, Yu L, 75. Ilarregui JM, Croci DO, Bianco GA, wabara I, Yamanaka T, et al. Human ga- Sharma BB, Kuwabara I, et al. Criti- Toscano MA, Salatino M, Vermeulen lectin-3 is a novel chemoattractant for cal role of galectin-3 in phagocytosis ME, et al. Tolerogenic signals delivered monocytes and macrophages. J Immunol. by macrophages. J Clin Invest. 2003 by dendritic cells to T cells through a 2000 Aug;165(4):2156–64. Aug;112(3):389–97. galectin-1-driven immunoregulatory 85. Hsu DK, Chernyavsky AI, Chen HY, 96. MacKinnon AC, Farnworth SL, Hod- circuit involving interleukin 27 and Yu L, Grando SA, Liu FT. Endogenous kinson PS, Henderson NC, Atkinson KM, interleukin 10. Nat Immunol. 2009 galectin-3 is localized in membrane Leffler H, et al. Regulation of alternative Sep;10(9):981–91. lipid rafts and regulates migration of macrophage activation by galectin-3. J 76. Toscano MA, Bianco GA, Ilarre- dendritic cells. J Invest Dermatol. 2009 Immunol. 2008 Feb;180(4):2650–8. gui JM, Croci DO, Correale J, Hernan- Mar;129(3):573–83. 97. Breuilh L, Vanhoutte F, Fontaine dez JD, et al. Differential glycosylation 86. Fukumori T, Takenaka Y, Yoshii T, J, van Stijn CM, Tillie-Leblond I, Cap- of TH1, TH2 and TH-17 effector cells Kim HR, Hogan V, Inohara H, et al. CD29 ron M, et al. Galectin-3 modulates im- selectively regulates susceptibil- and CD7 mediate galectin-3-induced mune and inflammatory responses ity to cell death. Nat Immunol. 2007 type II T-cell apoptosis. Cancer Res. 2003 during helminthic infection: impact of Aug;8(8):825–34. Dec;63(23):8302–11. galectin-3 deficiency on the functions 77. Saegusa J, Hsu DK, Chen HY, Yu L, 87. Stillman BN, Hsu DK, Pang M, of dendritic cells. Infect Immun. 2007 Fermin A, Fung MA, et al. Galectin-3 is Brewer CF, Johnson P, Liu FT, et al. Ga- Nov;75(11):5148–57. critical for the development of the aller- lectin-3 and galectin-1 bind distinct 98. Renkl AC, Wussler J, Ahrens T, gic inflammatory response in a mouse cell surface glycoprotein receptors to Thoma K, Kon S, Uede T, et al. Osteopon- model of atopic dermatitis. Am J Pathol. induce T cell death. J Immunol. 2006 tin functionally activates dendritic cells 2009 Mar;174(3):922–31. Jan;176(2):778–89. and induces their differentiation toward 78. Motran CC, Molinder KM, Liu SD, 88. Chen HY, Sharma BB, Yu L, Zuberi a Th1-polarizing phenotype. Blood. 2005 Poirier F, Miceli MC. Galectin-1 func- R, Weng IC, Kawakami Y, et al. Role Aug;106(3):946–55. tions as a Th2 cytokine that selectively of galectin-3 in mast cell functions: 99. Weiss JM, Renkl AC, Maier CS, Kim- induces Th1 apoptosis and promotes galectin-3-deficient mast cells exhibit mig M, Liaw L, Ahrens T, et al. Osteo- Th2 function. Eur J Immunol. 2008 impaired mediator release and defec- pontin is involved in the initiation of Nov;38(11):3015–27. tive JNK expression. J Immunol. 2006 cutaneous contact hypersensitivity by in- 79. Tsai CM, Chiu YK, Hsu TL, Lin IY, Oct;177(8):4991–7. ducing Langerhans and dendritic cell mi- Hsieh SL, Lin KI. Galectin-1 promotes im- 89. Hsu DK, Hammes SR, Kuwabara I, gration to lymph nodes. J Exp Med. 2001 munoglobulin production during plasma Greene WC, Liu FT. Human T lymphotropic Nov;194(9):1219–29. cell differentiation. J Immunol. 2008 virus-I infection of human T lymphocytes 100. Persy VP, Verhulst A, Ysebaert Oct;181(7):4570–9. induces expression of the beta-galac- DK, De Greef KE, De Broe ME. Reduced 80. Almkvist J, Dahlgren C, Leffler H, toside-binding lectin, galectin-3. Am J postischemic macrophage infiltration Karlsson A. Activation of the neutrophil Pathol. 1996 May;148(5):1661–70. and interstitial fibrosis in osteopon- nicotinamide adenine dinucleotide phos- 90. Dong S, Hughes RC. Galectin-3 stim- tin knockout mice. Kidney Int. 2003 phate oxidase by galectin-1. J Immunol. ulates uptake of extracellular Ca2+ in Feb;63(2):543–53. 2002 Apr;168(8):4034–41. human Jurkat T-cells. FEBS Lett. 1996 101. Giachelli CM, Giachelli CM, Lom- 81. Garin MI, Chu CC, Golshayan D, Oct;395(2–3):165–9. bardi D, Johnson RJ, Murry CE, Almeida Cernuda-Morollón E, Wait R, Lechler RI. 91. Li Y, Komai-Koma M, Gilchrist DS, M. Evidence for a role of osteopontin in Galectin-1: a key effector of regulation Hsu DK, Liu FT, Springall T, et al. Galec- macrophage infiltration in response to mediated by CD4+CD25+ T cells. Blood. tin-3 is a negative regulator of lipopoly- pathological stimuli in vivo. Am J Pathol. 2007 Mar;109(5):2058–65. saccharide-mediated inflammation. J 1998 Feb;152(2):353–8. 82. Wang J, Lu ZH, Gabius HJ, Immunol. 2008 Aug;181(4):2781–9. 102. Atai NA, Bansal M, Lo C, Bosman J, Rohowsky-Kochan C, Ledeen RW, Wu 92. Karlsson A, Follin P, Leffler H, Tigchelaar W, Bosch KS, et al. Osteopon- G. Cross-linking of GM1 ganglioside by Dahlgren C. Galectin-3 activates the tin is up-regulated and associated with

Licensee OA Publishing London 2013. Creative Commons Attribution License (CC-BY)

For citation purposes: Ruhmann M, Midwood KS. The pro-inflammatory niche: how the extracellular matrix drives

Review

neutrophil and macrophage infiltration the extracellular matrix protein tenascin. a pathway to generate regulatory T cells in glioblastoma. Immunology. 2011 J Immunol. 1994 Jun;152(11):5199–207. from human CD4+ CD25- T cells in Jan;132(1):39–48. 113. Hibino S, Kato K, Kudoh S, Yagita response to inflammation. J Immunol. 103. Nystrom T, Duner P. Hultgardh- H, Okumura K. Tenascin suppresses 2006 Sep;177(6):3534–41. Nilsson, A. A constitutive endogenous CD3-mediated T cell activation. Bio- 124. Yamauchi Y, Kuroki M, Imakiire osteopontin production is important for chem Biophys Res Commun. 1998 T, Abe H, Uchida H, Beppu R, et al. macrophage function and differentiation. Sep;250(1):119–24. Thrombospondin-1 differentially reg- Exp Cell Res. 2007 Apr;313(6):1149–60. 114. Ruhmann M, Piccinini AM, Kong ulates release of IL-6 and IL-10 by 104. Ashkar S, Weber GF, Panoutsako- PL, Midwood KS. Endogenous activation human monocytic cell line U937. Bio- poulou V, Sanchirico ME, Jansson M, of adaptive immunity: tenascin-C drives chem Biophys Res Commun. 2002 Zawaideh S, et al. Eta-1 (osteopontin): interleukin-17 synthesis in murine ar- Feb;290(5):1551–7. an early component of type-1 (cell- thritic joint disease. Arthritis Rheum. 125. Armant M, Avice MN, Hermann P, mediated) immunity. Science. 2000 2012 Jul;64(7):2179–90. Rubio M, Kiniwa M, Delespesse G, et al. Feb;287(5454):860–4. 115. Piccinini AM, Midwood KS. En- CD47 ligation selectively downregulates 105. Shinohara ML, Lu L, Bu J, Werneck dogenous control of immunity against human interleukin 12 production. J Exp MB, Kobayashi KS, Glimcher LH, et al. infection: tenascin-C regulates TLR4-me- Med. 1999 Oct;190(8):1175–82. Osteopontin expression is essential for diated inflammation via microRNA-155. 126. Demeure CE, Tanaka H, Mateo interferon-alpha production by plas- Cell Rep. 2012 Oct;2(4):914–26. V, Rubio M, Delespesse G, Sarfati M. macytoid dendritic cells. Nat Immunol. 116. Patel L, Sun W, Glasson SS, Mor- CD47 engagement inhibits cytokine 2006 May;7(5):498–506. ris EA, Flannery CR, Chockalingam PS. production and maturation of hu- 106. Sangaletti S, Gioiosa L, Guiducci Tenascin-C induces inflammatory me- man dendritic cells. J Immunol. 2000 C, Rotta G, Rescigno M, Stoppacciaro diators and matrix degradation in osteo- Feb;164(4):2193–9. A, et al. Accelerated dendritic-cell arthritic cartilage. BMC Musculoskelet 127. Doyen V, Rubio M, Braun D, Nakajima migration and T-cell priming in Disord. 2011 Jul;12:164. T, Abe J, Saito H, et al. Thrombospondin 1 SPARC-deficient mice. J Cell Sci. 2005 117. Liu R, He Y, Li B, Liu J, Ren Y, Han is an autocrine negative regulator of hu- Aug;118(Pt 16):3685–94. W, et al. Tenascin-C produced by oxidized man dendritic cell activation. J Exp Med. 107. Piconese S, Costanza M, Tripodo LDL-stimulated macrophages increases 2003 Oct;198(8):1277–83. C, Sangaletti S, Musio S, Pittoni P, et al. foam cell formation through Toll-like 128. Moodley Y, Rigby P, Bundell C, The matricellular protein SPARC sup- receptor-4. Mol Cells. 2012 Jul;34(1): Bunt S, Hayashi H, Misso N, et al. Mac- ports follicular dendritic cell networking 35–41. rophage recognition and phagocytosis toward Th17 responses. J Autoimmun. 118. Yabkowitz R, Dixit VM, Guo N, Rob- of apoptotic fibroblasts is critically de- 2011 Dec;37(4):300–10. erts DD, Shimizu Y. Activated T-cell adhe- pendent on fibroblast-derived thrombo- 108. Ruegg CR, Chiquet-Ehrismann R, sion to thrombospondin is mediated by spondin 1 and CD36. Am J Pathol. 2003 Alkan SS. Tenascin an extracellular ma- the alpha 4 beta 1 (VLA-4) and alpha 5 Mar;162(3):771–9. trix protein, exerts immunomodulatory beta 1 (VLA-5) integrins. J Immunol. 129. Ortiz-Masià D, Díez I, Calatayud S, activities. Proc Natl Acad Sci USA. 1989 1993 Jul:151(1):149–58. Hernández C, Cosín-Roger J, Hinojosa J, Oct;86(19):7437–41. 119. Mansfield PJ, Suchard SJ. Throm- et al. Induction of CD36 and thrombos- 109. Talts JF, Wirl G, Dictor M, Muller bospondin promotes chemotaxis pondin-1 in macrophages by hypoxia- WJ, Fässler R. Tenascin-C modulates and haptotaxis of human peripheral inducible factor 1 and its relevance in tumor stroma and monocyte/macro- blood monocytes. J Immunol. 1994 the inflammatory process. PLoS One. phage recruitment but not tumor growth Nov;153(9):4219–29. 2012;7(10):e48535. or metastasis in a mouse strain with 120. Mansfield PJ, Suchard SJ. Thrombo- 130. Saban Bock F, Chauhan SK, Masli spontaneous mammary cancer. J Cell Sci. spondin promotes both chemotaxis and S, Dana R. Thrombospondin-1 derived 1999 Jun;112(Pt12):1855–64. haptotaxis in neutrophil-like HL-60 cells. from APCs regulates their capacity 110. Loike JD, Cao L, Budhu S, Hoffman S, J Immunol. 1993 Mar;150(5):1959–70. for allosensitization. J Immunol. 2010 Silverstein SC. Blockade of alpha 5 beta 1 121. Vallejo AN, Mügge LO, Klimiuk Oct;185(8):4691–7. integrins reverses the inhibitory effect of PA, Weyand CM, Goronzy JJ. Cen- 131. Krispin A, Bledi Y, Atallah M, tenascin on chemotaxis of human mono- tral role of thrombospondin-1 in the Trahtemberg U, Verbovetski I, Nahari cytes and polymorphonuclear leukocytes activation and clonal expansion of in- E, et al. Apoptotic cell thrombospon- through three-dimensional gels of extra- flammatory T cells. J Immunol. 2000 din-1 and heparin-binding domain lead cellular matrix proteins. J Immunol. 2001 Mar;164(6):2947–54. to dendritic-cell phagocytic and toler- Jun;166(12):7534–42. 122. Johansson U, Higginbottom K, izing states. Blood. 2006 Nov;108(10): 111. Parekh K, Ramachandran S, Cooper Londei M. CD47 ligation induces a rapid 3580–9. J, Bigner D, Patterson A, Mohanakumar T. caspase-independent apoptosis-like 132. Li Z, He L, Wilson K, Roberts Tenascin-C, over expressed in lung can- cell death in human monocytes and D. Thrombospondin-1 inhibits TCR- cer down regulates effector functions dendritic cells. Scand J Immunol. 2004 mediated T lymphocyte early activation. of tumor infiltrating lymphocytes. Lung Jan;59(1):40–9. J Immunol. 2001 Feb;166(4):2427–36. Cancer. 2005 Jan;47(1):17–29. 123. Grimbert P, Bouguermouh S, Baba 133. Lange-Asschenfeldt B, Weninger 112. Hemesath TJ, Marton LS, Stefans- N, Nakajima T, Allakhverdi Z, Braun D, W, Velasco P, Kyriakides TR, von An- son K. Inhibition of T cell activation by et al. Thrombospondin/CD47 interaction: drian UH, Bornstein P, et al. Increased

Licensee OA Publishing London 2013. Creative Commons Attribution License (CC-BY)

For citation purposes: Ruhmann M, Midwood KS. The pro-inflammatory niche: how the extracellular matrix drives

Review

and prolonged inflammation and rheumatoid arthritis. Arthritis Rheum. 152. Forsman H, Islander U, Andréasson angiogenesis in delayed-type hyper- 2000 Apr;43(4):775–90. E, Andersson A, Onnheim K, Karlström A, sensitivity reactions elicited in the skin 143. Zhang Q, Wu J, Cao Q, Xiao L, Wang et al. Galectin 3 aggravates joint inflamma- of thrombospondin-2--deficient mice. L, He D, et al. A critical role of Cyr61 in tion and destruction in antigen-induced Blood. 2002 Jan;99(2):538–45. interleukin-17-dependent proliferation arthritis. Arthritis Rheum. 2011 134. Nakamura S, Kamihagi K, Satakeda of fibroblast-like synoviocytes in rheu- Feb;63(2):445–54. H, Katayama M, Pan H, Okamoto H, et al. matoid arthritis. Arthritis Rheum. 2009 153. Fan K, Dai J, Wang H, Wei H, Cao Enhancement of SPARC (osteonectin) Dec;60(12):3602–12. Z, Hou S, et al. Treatment of collagen-in- synthesis in arthritic cartilage. Increased 144. Kok SH, Lin LD, Hou KL, Hong CY, duced arthritis with an anti-osteopontin levels in synovial fluids from patients Chang CC, Hsiao M, et al. Simvastatin monoclonal antibody through promotion with rheumatoid arthritis and regulation inhibits cysteine-rich protein 61 expres- of apoptosis of both murine and human by growth factors and cytokines in chon- sion in rheumatoid arthritis synovial activated T cells. Arthritis Rheum. 2008 drocyte cultures. Arthritis Rheum. 1996 fibroblasts through the regulation of Jul;58(7):2041–52. Apr;39(4):539–51. sirtuin-1/FoxO3a signaling. Arthritis 154. Yamamoto N, Sakai F, Kon S, Morim- 135. Cutolo M, Picasso M, Ponassi M, Sun Rheum. 2013 Mar;65(3):639–49. oto J, Kimura C, Yamazaki H, et al. Essen- MZ, Balza E. Tenascin and fibronectin 145. Lin J, Zhou Z, Huo R, Xiao L, Ouy- tial role of the cryptic epitope SLAYGLR distribution in human normal and path- ang G, Wang L, et al. Cyr61 induces IL-6 within osteopontin in a murine model of ological synovium. J Rheumatol. 1992 production by fibroblast-like synovio- rheumatoid arthritis. J Clin Invest. 2003 Sep;19(9):1439–47. cytes promoting Th17 differentiation in Jul;112(2):181–8. 136. Chevalier X, Groult N, Larget- rheumatoid arthritis. J Immunol. 2012 155. Nozawa K, Fujishiro M, Kawasaki M, Piet B, Zardi L, Hornebeck W. Tenas- Jun;188(11):5776–84. Yamaguchi A, Ikeda K, Morimoto S, et al. cin distribution in articular cartilage 146. Take Y, Nakata K, Hashimoto J, Inhibition of connective tissue growth from normal subjects and from pa- Tsuboi H, Nishimoto N, Ochi T, et al. factor ameliorates rheumatoid arthri- tients with osteoarthritis and rheuma- Specifically modified osteopontin in tis in a murine model. Arthritis Rheum. toid arthritis. Arthritis Rheum. 1994 rheumatoid arthritis fibroblast-like 2013 Feb. Jul;37(7):1013–22. synoviocytes supports interaction with 156. Nozawa K, Fujishiro M, Kawasaki 137. McCachren SS, Lightner VA. Ex- B cells and enhances production of M, Kaneko H, Iwabuchi K, Yanagida M, pression of human tenascin in synovi- interleukin-6. Arthritis Rheum. 2009 et al. Connective tissue growth factor tis and its regulation by interleukin-1. Dec;60(12):3591–601. promotes articular damage by increased Arthritis Rheum. 1992 Oct;35(10): 147. Chen G, Zhang X, Li R, Fang L, Niu osteoclastogenesis in patients with 1185–96. X, Zheng Y, et al. Role of osteopontin in rheumatoid arthritis. Arthritis Res Ther. 138. Salter DM. Tenascin is increased synovial Th17 differentiation in rheu- 2009;11(6):R174. in cartilage and synovium from ar- matoid arthritis. Arthritis Rheum. 2010 157. Rico MC, Castaneda JL, Manns thritic knees. Br J Rheumatol. 1993 Oct;62(10):2900–8. JM, Uknis AB, Sainz IM, Safadi FF, et al. Sep;32(9):780–6. 148. Yumoto K, Ishijima M, Rittling SR, Amelioration of inflammation, angio- 139. Petrow PK, Hummel KM, Schedel Tsuji K, Tsuchiya Y, Kon S, et al. Osteo- genesis and CTGF expression in an ar- J, Franz JK, Klein CL, Müller-Ladner U, pontin deficiency protects joints against thritis model by a TSP1-derived peptide et al. Expression of osteopontin mes- destruction in anti-type II collagen an- treatment. J Cell Physiol. 2007 May; senger RNA and protein in rheumatoid tibody-induced arthritis in mice. Proc 211(2):504–12. arthritis: effects of osteopontin on the Natl Acad Sci U S A. 2002 Apr;99(7): 158. Manns JM, Uknis AB, Rico MC, release of collagenase 1 from articu- 4556–61. Agelan A, Castaneda J, Arango I, et al. lar chondrocytes and synovial fibro- 149. Rabinovich GA, Daly G, Dreja H, A peptide from thrombospondin 1 blasts. Arthritis Rheum. 2000 Jul;43(7): Tailor H, Riera CM, Hirabayashi J, et al. modulates experimental erosive ar- 1597–605. Recombinant galectin-1 and its genetic thritis by regulating connective tissue 140. Ohshima S, Kuchen S, Seemayer CA, delivery suppress collagen-induced ar- growth factor. Arthritis Rheum. 2006 Kyburz D, Hirt A, Klinzing S, et al. Ga- thritis via T cell apoptosis. J Exp Med. Aug;54(8):2415–22. lectin 3 and its binding protein in rheu- 1999 Aug;190(3):385–98. 159. Jou IM, Shiau AL, Chen SY, Wang matoid arthritis. Arthritis Rheum. 2003 150. Wang CR, Shiau AL, Chen SY, Cheng CR, Shieh DB, Tsai CS, et al. Throm- Oct;48(10):2788–95. ZS, Li YT, Lee CH, et al. Intra-articular bospondin 1 as an effective gene 141. Goh FG, Piccinini AM, Krausgruber lentivirus-mediated delivery of galec- therapeutic strategy in collagen-in- T, Udalova IA, Midwood KS. Transcrip- tin-3 shRNA and galectin-1 gene ame- duced arthritis. Arthritis Rheum. 2005 tional regulation of the endogenous dan- liorates collagen-induced arthritis. Gene Jan;52(1):339–44. ger signal tenascin-C: a novel autocrine Ther. 2010 Oct;17(10):1225–33. 160. Haas CS, Creighton CJ, Pi X, Maine I, loop in inflammation. J Immunol. 2010 151. Filer A, Bik M, Parsonage GN, Fitton Koch AE, Haines GK, et al. Identification Mar;184(5):2655–62. J, Trebilcock E, Howlett K, et al. Galectin of genes modulated in rheumatoid ar- 142. Stuhlmuller B, Ungethüm U, 3 induces a distinctive pattern of cyto- thritis using complementary DNA mi- Scholze S, Martinez L, Backhaus M, kine and chemokine production in rheu- croarray analysis of lymphoblastoid Kraetsch HG, et al. Identification matoid synovial fibroblasts via selective B cell lines from disease-discordant of known and novel genes in acti- signaling pathways. Arthritis Rheum. monozygotic twins. Arthritis Rheum. vated monocytes from patients with 2009 Jun;60(6):1604–14. 2006 Jul;54(7):2047–60.

Licensee OA Publishing London 2013. Creative Commons Attribution License (CC-BY)

For citation purposes: Ruhmann M, Midwood KS. The pro-inflammatory niche: how the extracellular matrix drives

Review

161. Wu PH, Lin SK, Lee BS, Kok SH, 171. Schofield R. The relationship development in mouse bone marrow. Wang JH, Hou KL, et al. Epigallocatechin- between the spleen colony-forming cell Blood. 2011 Jun;117(24):6552–61. 3-gallate diminishes cytokine-stimulated and the haemopoietic stem cell. Blood 184. Wong GS, Rustgi AK. Matricel- Cyr61 expression in human osteoblastic Cells. 1978;4(1–2):7–25. lular proteins: priming the tumour cells: a therapeutic potential for 172. Lo Celso C, Scadden DT. The haema- microenvironment for cancer develop- arthritis. Rheumatology (Oxford). 2012 topoietic stem cell niche at a glance. J Cell ment and metastasis. Br J Cancer. 2013 Nov;51(11):1953–65. Sci. 2011 Nov;124(Pt 21):3529–35. Mar;108(4):755–61. 162. Tanaka I, Morikawa M, Okuse T, Shi- 173. Lobo NA, Shimono Y, Qian D, Clarke 185. Oskarsson T, Massague J. Extracel- rakawa M, Imai K. Expression and regu- MF. The biology of cancer stem cells. lular matrix players in metastatic niches. lation of WISP2 in rheumatoid arthritic Annu Rev Cell Dev Biol. 2007;23:675–99. EMBO J. 2012 Jan;31(2):254–6. synovium. Biochem Biophys Res Com- 174. Cabarcas SM, Mathews LA, Farrar 186. Tilli TM, Franco VF, Robbs BK, mun. 2005 Sep;334(4):973–8. WL. The cancer stem cell niche--there Wanderley JL, da Silva FR, de Mello 163. Cheon H, Boyle DL, Firestein GS. goes the neighborhood? Int J Cancer. KD, et al. Osteopontin-c splicing iso- Wnt1 inducible signaling pathway pro- 2011 Nov;129(10):2315–27. form contributes to ovarian cancer tein-3 regulation and microsatellite 175. Paget S. The distribution of sec- progression. Mol Cancer Res. 2011 structure in arthritis. J Rheumatol. 2004 ondary growths in cancer of the breast. Mar;9(3):280–93. Nov;31(11):2106–14. 1889. Cancer Metastasis Rev. 1989 187. Tilli TM, Mello KD, Ferreira LB, Ma- 164. Huang YJ, Shiau AL, Chen SY, Chen Aug;8(2):98–101. tos AR, Accioly MT, Faria PA, et al. Both YL, Wang CR, Tsai CY, et al. Multivalent 176. Psaila B, Lyden D. The metastatic osteopontin-c and osteopontin-b splic- structure of galectin-1-nanogold com- niche: adapting the foreign soil. Nat Rev ing isoforms exert pro-tumorigenic roles plex serves as potential therapeutics for Cancer. 2009 Apr;9(4):285–93. in prostate cancer cells. Prostate. 2012 rheumatoid arthritis by enhancing re- 177. Lu P, Weaver VM, Werb Z. The Nov;72(15):1688–99. ceptor clustering. Eur Cell Mater. 2012 extracellular matrix: a dynamic niche 188. Oskarsson T, Acharyya S, Zhang XH, Mar;23:170–81. in cancer progression. J Cell Biol. 2012 Vanharanta S, Tavazoie SF, Morris PG, 165. Cedeno-Laurent F, Barthel SR, Op- Feb;196(4):395–406. et al. Breast cancer cells produce tenas- perman MJ, Lee DM, Clark RA, Dimitroff 178. Stier S, Ko Y, Forkert R, Lutz C, cin C as a metastatic niche component CJ. Development of a nascent galectin-1 Neuhaus T, Grünewald E, et al. Osteo- to colonize the lungs. Nat Med. 2011 chimeric molecule for studying the role pontin is a hematopoietic stem cell niche Jun;17(7):867–74. of leukocyte galectin-1 ligands and component that negatively regulates 189. Schutze N, Noth U, Schneidereit immune disease modulation. J Immunol. stem cell pool size. J Exp Med. 2005 J, Hendrich C, Jakob F. Differential ex- 2010 Oct;185(8):4659–72. Jun;201(11):1781–91. pression of CCN-family members in 166. Neidhart M, Zaucke F, von Knoch 179. Nilsson SK, Johnston HM, Whitty primary human bone marrow-derived R, Jüngel A, Michel BA, Gay RE, et al, Ga- GA, Williams B, Webb RJ, Denhardt DT, mesenchymal stem cells during osteo- lectin-3 is induced in rheumatoid arthri- et al. Osteopontin, a key component genic, chondrogenic and adipogenic dif- tis synovial fibroblasts after adhesion to of the hematopoietic stem cell niche ferentiation. Cell Commun Signal. 2005 cartilage oligomeric matrix protein. Ann and regulator of primitive hemato- Mar;3(1):5. Rheum Dis. 2005 Mar;64(3):419–24. poietic progenitor cells. Blood. 2005 190. Si W, Kang Q, Luu HH, Park JK, Luo 167. Seki M, Sakata KM, Oomizu S, Ari- Aug;106(4):1232–9. Q, Song WX, Jiang W, et al. CCN1/Cyr61 kawa T, Sakata A, Ueno M, et al. Ben- 180. Nakamura-Ishizu A, Okuno Y, is regulated by the canonical Wnt signal eficial effect of galectin 9 on rheumatoid Omatsu Y, Okabe K, Morimoto J, Uede and plays an important role in Wnt3A-in- arthritis by induction of apoptosis of sy- T, et al. Extracellular matrix protein duced osteoblast differentiation of mes- novial fibroblasts. Arthritis Rheum. 2007 tenascin-C is required in the bone mar- enchymal stem cells. Mol Cell Biol. 2006 Dec;56(12):3968–76. row microenvironment primed for he- Apr;26(8):2955–64. 168. Hasegawa M, Nakoshi Y, Muraki matopoietic regeneration. Blood. 2012 191. Schutze N, Schenk R, Fiedler J, M, Sudo A, Kinoshita N, Yoshida T, et al. Jun;119(23):5429–37. Mattes T, Jakob F, Brenner RE. CYR61/ Expression of large tenascin-C splice 181. Klein G, Beck S, Müller CA. Tenas- CCN1 and WISP3/CCN6 are chemoat- variants in synovial fluid of patients with cin is a cytoadhesive extracellular matrix tractive ligands for human multipotent rheumatoid arthritis. J Orthop Res. 2007 component of the human hematopoi- mesenchymal stroma cells. BMC Cell May;25(5):563–8. etic microenvironment. J Cell Biol. 1993 Biol. 2007 Oct;8:45. 169. Page TH, Charles PJ, Piccinini AM, Nov;123(4):1027–35. 192. Schutze N, Kunzi-Rapp K, Wage- Nicolaidou V, Taylor PC, Midwood KS. 182. Seiffert M, Beck SC, Schermutzki manns R, Nöth U, Jatzke S, Jakob F. Expres- Raised circulating tenascin-C in rheuma- F, Müller CA, Erickson HP, Klein G. sion, purification, and functional testing toid arthritis. Arthritis Res Ther. 2012 Mitogenic and adhesive effects of tenas- of recombinant CYR61/CCN1. Protein Nov;14(6):R260. cin-C on human hematopoietic cells are Expr Purif. 2005 Jul;42(1):219–25. 170. Koch AE, Szekanecz Z, Friedman J, mediated by various functional domains. 193. Zuo GW, Kohls CD, He BC, Chen L, Haines GK, Langman CB, Bouck NP. Effects Matrix Biol. 1998 Apr;17(1):47–63. Zhang W, Shi Q, et al. The CCN proteins: of thrombospondin-1 on disease course 183. Mourcin F, Breton C, Tellier J, important signaling mediators in stem and angiogenesis in rat adjuvant-induced Narang P, Chasson L, Jorquera A, et al. cell differentiation and tumorigenesis. arthritis. Clin Immunol Immunopathol. Galectin-1-expressing stromal cells Histol Histopathol. 2010 Jun;25(6): 1998 Feb;86(2):199–208. constitute a specific niche for pre-BII cell 795–806.

Licensee OA Publishing London 2013. Creative Commons Attribution License (CC-BY)

For citation purposes: Ruhmann M, Midwood KS. The pro-inflammatory niche: how the extracellular matrix drives

Review

194. Nguyen N, Kuliopulos A, Graham RA, Biochem Biophys Res Commun. 2007 pression of galectin-1 mRNA correlates Covic L. Tumor-derived Cyr61(CCN1) pro- May;357(1):20–5. with the malignant potential of human motes stromal matrix metalloproteinase-1 204. Safadi FF, Xu J, Smock SL, Kanaan gliomas and expression of antisense production and protease-activated RA, Selim AH, Odgren PR, et al. Expres- galectin-1 inhibits the growth of 9 receptor 1-dependent migration of sion of connective tissue growth factor glioma cells. J Neurosci Res. 2000 breast cancer cells. Cancer Res. 2006 in bone: its role in osteoblast prolifera- Mar;59(6):722–30. Mar;66(5):2658–65. tion and differentiation in vitro and bone 214. Banh A, Zhang J, Cao H, Bou- 195. Babic AM, Kireeva ML, Kolesn- formation in vivo. J Cell Physiol. 2003 ley DM, Kwok S, Kong C, et al. Tumor ikova TV, Lau LF. CYR61, a product of a Jul;196(1):51–62. galectin-1 mediates tumor growth growth factor-inducible immediate early 205. Chang CC, Yang MH, Lin BR, Chen and metastasis through regulation gene, promotes angiogenesis and tumor ST, Pan SH, Hsiao M, et al. CCN2 inhibits of T-cell apoptosis. Cancer Res. 2011 growth. Proc Natl Acad Sci USA. 1998 lung cancer metastasis through promot- Jul;71(13):4423–31. May;95(11):6355–60. ing DAPK-dependent anoikis and induc- 215. Dalotto-Moreno T, Croci DO, Cerli- 196. Xie D, Yin D, Tong X, O’Kelly J, ing EGFR degradation. Cell Death Differ. ani JP, Martinez-Allo VC, Dergan-Dylon S, Mori A, Miller C, et al. Cyr61 is over- 2013 Mar;20(3):443–55. Méndez-Huergo SP, et al. Targeting galec- expressed in gliomas and involved 206. Bennewith KL, Huang X, Ham CM, tin-1 overcomes breast cancer-associated in integrin-linked kinase-mediated Graves EE, Erler JT, Kambham N, et al. immunosuppression and prevents Akt and beta-catenin-TCF/Lef sig- The role of tumor cell-derived connec- metastatic disease. Cancer Res. 2013 naling pathways. Cancer Res. 2004 tive tissue growth factor (CTGF/CCN2) Feb;73(3):1107–17. Mar;64(6):1987–96. in pancreatic tumor growth. Cancer Res. 216. Hsu YL, Wu CY, Hung JY, Lin YS, 197. Dobroff AS, Wang H, Melnikova 2009 Feb;69(3):775–84. Huang MS, Kuo PL. Galectin-1 promotes VO, Villares GJ, Zigler M, Huang L, 207. Aikawa T, Gunn J, Spong SM, Klaus lung cancer tumor metastasis by potenti- et al. Silencing cAMP-response ele- SJ, Korc M. Connective tissue growth fac- ating integrin alpha6beta4 and Notch1/ ment-binding protein (CREB) iden- tor-specific antibody attenuates tumor Jagged2 signaling pathway. Carcinogen- tifies CYR61 as a tumor suppressor growth, metastasis, and angiogenesis esis. 2013 Mar. gene in melanoma. J Biol Chem. 2009 in an orthotopic mouse model of pan- 217. Krugluger W, Frigeri LG, Lucas Sep;284(38):26194–206. creatic cancer. Mol Cancer Ther. 2006 T, Schmer M, Förster O, Liu FT, et al. 198. Feng P, Wang B, Ren EC. Cyr61/ May;5(5):1108–16. Galectin-3 inhibits granulocyte-mac- CCN1 is a tumor suppressor in human 208. Pedemonte E, Benvenuto F, Casa- rophage colony-stimulating factor hepatocellular carcinoma and involved zza S, Mancardi G, Oksenberg JR, Uc- (GM-CSF)-driven rat bone marrow cell in DNA damage response. Int J Biochem celli A, et al. The molecular signature proliferation and GM-CSF-induced gene Cell Biol. 2008;40(1):98–109. of therapeutic mesenchymal stem cells transcription. Immunobiology. 1997 199. Cicha I, Garlichs CD, Daniel WG, exposes the architecture of the hemato- Jun;197(1):97–109. Goppelt-Struebe M. Activated human poietic stem cell niche synapse. BMC Ge- 218. Oliveira FL, Frazão P, Chammas R, platelets release connective tissue nomics. 2007 Mar;8:65. Hsu DK, Liu FT, Borojevic R, et al. Kinet- growth factor. Thromb Haemost. 2004 209. Espeli M, Mancini SJ, Breton C, ics of mobilization and differentiation Apr;91(4):755–60. Poirier F, Schiff C. Impaired B-cell de- of lymphohematopoietic cells during 200. Lee CH, Shah B, Moioli EK, Mao JJ. velopment at the pre-BII-cell stage in ga- experimental murine schistosomiasis in CTGF directs fibroblast differentiation lectin-1-deficient mice due to inefficient galectin-3 -/- mice. J Leukoc Biol. 2007 from human mesenchymal stem/stromal pre-BII/stromal cell interactions. Blood. Aug;82(2):300–10. cells and defines connective tissue heal- 2009 Jun;113(23):5878–86. 219. Brand C, Oliveira FL, Ricon L, ing in a rodent injury model. J Clin Invest. 210. Vas V, Fajka-Boja R, Ion G, Du- Fermino ML, Boldrini LC, Hsu DK, 2010 Sep;120(9):3340–9. dics V, Monostori E, Uher F. Biphasic et al. The bone marrow compart- 201. Tong Z, Sant S, Khademhosseini effect of recombinant galectin-1 ment is modified in the absence of A, Jia X. Controlling the fibroblastic on the growth and death of early galectin-3. Cell Tissue Res. 2011 differentiation of mesenchymal stem hematopoietic cells. Stem Cells. 2005 Dec;346(3):427–37. cells via the combination of fibrous Feb;23(2):279–87. 220. Cay T. Immunhistochemical expres- scaffolds and connective tissue growth 211. Andersen H, Jensen ON, Moiseeva sion of galectin-3 in cancer: a review factor. Tissue Eng Part A. 2011 Nov;17 EP, Eriksen EF. A proteome study of se- of the literature. Turk Patoloji Derg. (21–22):2773–85. creted prostatic factors affecting osteo- 2012;28(1):1–10. 202. Wang JJ, Ye F, Cheng LJ, Shi YJ, Bao J, blastic activity: galectin-1 is involved in 221. Honjo Y, Nangia-Makker P, Inohara Sun HQ, et al. Osteogenic differentiation differentiation of human bone marrow H, Raz A. Down-regulation of galectin-3 of mesenchymal stem cells promoted stromal cells. J Bone Miner Res. 2003 suppresses tumorigenicity of human by overexpression of connective tissue Feb;18(2):195–203. breast carcinoma cells. Clin Cancer Res. growth factor. J Zhejiang Univ Sci B. 2009 212. Camby I, Le Mercier M, Lefranc F, 2001 Mar;7(3):661–8. May;10(5):355–67. Kiss R. Galectin-1: a small protein with 222. Hoyer KK, Pang M, Gui D, Shintaku 203. Ono M, Kubota S, Fujisawa T, major functions. Glycobiology. 2006 IP, Kuwabara I, Liu FT, et al. An anti- Sonoyama W, Kawaki H, Akiyama K, Nov;16(11):137R–157R. apoptotic role for galectin-3 in diffuse et al. Promotion of attachment of human 213. Yamaoka K, Mishima K, Na- large B-cell lymphomas. Am J Pathol. bone marrow stromal cells by CCN2. gashima Y, Asai A, Sanai Y, Kirino T. Ex- 2004 Mar;164(3):893–902.

Licensee OA Publishing London 2013. Creative Commons Attribution License (CC-BY)

For citation purposes: Ruhmann M, Midwood KS. The pro-inflammatory niche: how the extracellular matrix drives

Review

223. Takenaka Y, Inohara H, Yoshii T, in zebrafish. Cells Tissues Organs. et al. Identification of VEGF-regulated Oshima K, Nakahara S, Akahani S, et al. 2013;197(3):196–208. genes associated with increased lung Malignant transformation of thyroid fol- 234. Clark CJ, Sage EH. A prototypic metastatic potential: functional involve- licular cells by galectin-3. Cancer Lett. matricellular protein in the tumor ment of tenascin-C in tumor growth 2003 May;195(1):111–9. microenvironment--where there’s and lung metastasis. Oncogene. 2008 224. Le Marer N, Hughes RC. Effects of SPARC, there’s fire. J Cell Biochem. 2008 Sep;27(40):5373–84. the carbohydrate-binding protein ga- Jun;104(3):721–32. 245. O’Connell JT, Sugimoto H, Cooke lectin-3 on the invasiveness of human 235. Koblinski JE, Kaplan-Singer VG, MacDonald BA, Mehta AI, LeBleu VS, breast carcinoma cells. J Cell Physiol. BR, VanOsdol SJ, Wu M, Engbring et al. VEGF-A and Tenascin-C produced by 1996 Jul;168(1):51–8. JA, Wang S, et al. Endogenous osteo- S100A4+ stromal cells are important for 225. Grassinger J, Haylock DN, Storan nectin/SPARC/BM-40 expression in- metastatic colonization. Proc Natl Acad MJ, Haines GO, Williams B, Whitty GA, hibits MDA-MB-231 breast cancer Sci USA. 2011 Sep;108(38):16002–7. et al. Thrombin-cleaved osteopontin reg- cell metastasis. Cancer Res. 2005 246. Hancox RA, Allen MD, Holliday DL, ulates hemopoietic stem and progenitor Aug;65(16):7370–7. Edwards DR, Pennington CJ, Guttery cell functions through interactions with 236. Golembieski WA, Ge S, Nelson K, DS, et al. Tumour-associated tenascin- alpha9beta1 and alpha4beta1 integrins. Mikkelsen T, Rempel SA. Increased SPARC C isoforms promote breast cancer cell Blood. 2009 Jul;114(1):49–59. expression promotes U87 glioblastoma invasion and growth by matrix metal- 226. Rittling SR, Chambers AF. Role of invasion in vitro. Int J Dev Neurosci. 1999 loproteinase-dependent and indepen- osteopontin in tumour progression. Br Aug-Oct;17(5–6):463–72. dent mechanisms. Breast Cancer Res. J Cancer. 2004 May;90(10):1877–81. 237. Ledda MF, Adris S, Bravo AI, Kai- 2009;11(2):R24. 227. Takafuji V, Forgues M, Un- riyama C, Bover L, Chernajovsky Y, et al. 247. Huang JY, Cheng YJ, Lin YP, Lin HC, sworth E, Goldsmith P, Wang XW. An Suppression of SPARC expression by an- Su CC, Juliano R, et al. Extracellular ma- osteopontin fragment is essential tisense RNA abrogates the tumorigenic- trix of glioblastoma inhibits polarization for tumor cell invasion in hepato- ity of human melanoma cells. Nat Med. and transmigration of T cells: the role of cellular carcinoma. Oncogene. 2007 1997 Feb;3(2):171–6. tenascin-C in immune suppression. J Im- Sep;26(44):6361–71. 238. Brekken RA, Puolakkainen P, munol. 2010 Aug;185(3):1450–9. 228. Zhang A, Liu Y, Shen Y, Xu Y, Li Graves DC, Workman G, Lubkin SR, 248. Long MW, Dixit VM. Thrombospon- X. Osteopontin silencing by small in- Sage EH. Enhanced growth of tumors din functions as a cytoadhesion molecule terfering RNA induces apoptosis and in SPARC null mice is associated with for human hematopoietic progenitor suppresses invasion in human renal car- changes in the ECM. J Clin Invest. 2003 cells. Blood. 1990 Jun;75(12):2311–8. cinoma Caki-1 cells. Med Oncol. 2010 Feb;111(4):487–95. 249. Bailey Dubose K, Zayzafoon M, Mur- Dec;27(4):1179–84. 239. Chlenski A, Liu S, Guerrero LJ, phy-Ullrich JE. Thrombospondin-1 inhib- 229. Courter D, Cao H, Kwok S, Kong C, Yang Q, Tian Y, Salwen HR, et al. SPARC its osteogenic differentiation of human Banh A, Kuo P, et al. The RGD domain expression is associated with impaired mesenchymal stem cells through latent of human osteopontin promotes tumor tumor growth, inhibited angiogenesis TGF-beta activation. Biochem Biophys growth and metastasis through activa- and changes in the extracellular matrix. Res Commun. 2012 Jun;422(3):488–93. tion of survival pathways. PLoS One. Int J Cancer. 2006 Jan;118(2):310–6. 250. Long MW, Briddell R, Walter AW, 2010 Mar;5(3):e9633. 240. Ekblom M, Fässler R, Tomasini- Bruno E, Hoffman R. Human hemato- 230. Siva K, Jaako P, Miharada K, Rörby Johansson B, Nilsson K, Ekblom P. Down- poietic stem cell adherence to cytokines E, Ehinger M, Karlsson G, et al. SPARC is regulation of tenascin expression by and matrix molecules. J Clin Invest. 1992 dispensable for murine hematopoiesis, glucocorticoids in bone marrow stromal Jul;90(1):251–5. despite its suspected pathophysiological cells and in fibroblasts. J Cell Biol. 1993 251. Chen YZ, Incardona F, Legrand role in 5q-myelodysplastic syndrome. Nov;123(4):1037–45. C, Momeux L, Caen J, Han ZC. Throm- Leukemia. 2012 Nov;26(11):2416–9. 241. Sakai T, Ohta M, Kawakatsu H, Fu- bospondin, a negative modulator of 231. Delany AM, Kalajzic I, Bradshaw AD, rukawa Y, Saito M. Tenascin-C induction megakaryocytopoiesis. J Lab Clin Med. Sage EH, Canalis E. Osteonectin-null mu- in Whitlock-Witte culture: a relevant role 1997 Feb;129(2):231–8. tation compromises osteoblast formation, of the thiol moiety in lymphoid-lineage 252. Sargiannidou I, Zhou J, Tuszynski maturation, and survival. Endocrinology. differentiation. Exp Cell Res. 1995 GP. The role of thrombospondin-1 2003 Jun;144(6):2588–96. Apr;217(2):395–403. in tumor progression. Exp Biol Med 232. Lehmann S, O’Kelly J, Raynaud S, 242. Ohta M, Ohta M, Sakai T, Saga (Maywood). 2001 Sep;226(8):726–33. Funk SE, Sage EH, Koeffler HP. Common Y, Aizawa S, Saito M, et al. Suppres- 253. Rofstad EK, Graff BA. Thrombos- deleted genes in the 5q- syndrome: sion of hematopoietic activity in te- pondin-1-mediated metastasis suppres- thrombocytopenia and reduced erythroid nascin-C-deficient mice. Blood. 1998 sion by the primary tumor in human colony formation in SPARC null mice. Jun;91(11):4074–83. melanoma xenografts. J Invest Dermatol. Leukemia. 2007 Sep;21(9):1931–6. 243. Midwood KS, Orend G. The role of 2001 Nov;117(5):1042–9. 233. Ceinos RM, Torres-Nuñez E, Cham- tenascin-C in tissue injury and tumori- 254. Yee KO, Connolly CM, Duquette M, orro R, Novoa B, Figueras A, Ruane NM, genesis. J Cell Commun Signal. 2009 Kazerounian S, Washington R, Lawler Rotllant J, et al. Critical role of the ma- Dec;3(3–4):287–310. J. The effect of thrombospondin-1 on tricellular protein SPARC in mediating 244. Calvo A, Catena R, Noble MS, Car- breast cancer metastasis. Breast Cancer erythroid progenitor cell development bott D, Gil-Bazo I, Gonzalez-Moreno O, Res Treat. 2009 Mar;114(1):85–96.

Licensee OA Publishing London 2013. Creative Commons Attribution License (CC-BY)

For citation purposes: Ruhmann M, Midwood KS. The pro-inflammatory niche: how the extracellular matrix drives

Review

255. Firlej V, Mathieu JR, Gilbert C, 265. Hawighorst T, Velasco P, Streit M, treatment of malignant gliomas by direct Lemonnier L, Nakhlé J, Gallou-Kabani Hong YK, Kyriakides TR, Brown LF, et al. infusion of specific monoclonal antibod- C, et al. Thrombospondin-1 triggers cell Thrombospondin-2 plays a protective ies labeled with 131I: comparison of the migration and development of advanced role in multistep carcinogenesis: a novel results obtained in recurrent and newly prostate tumors. Cancer Res. 2011 host anti-tumor defense mechanism. diagnosed tumors. Cancer Res. 1995 Dec;71(24):7649–58. EMBO J. 2001 Jun;20(11):2631–40. Dec;55(23 Suppl):5952s–5956s. 256. Martin-Manso G, Galli S, Ridnour LA, 266. Streit M, Riccardi L, Velasco P, 277. Riva P, Franceschi G, Frattarelli M, Tsokos M, Wink DA, Roberts DD. Throm- Brown LF, Hawighorst T, Bornstein Lazzari S, Riva N, Giuliani G, et al. Loco- bospondin 1 promotes tumor macrophage P, et al. Thrombospondin-2: a potent regional radioimmunotherapy of high- recruitment and enhances tumor cell endogenous inhibitor of tumor growth grade malignant gliomas using specific cytotoxicity of differentiated U937 cells. and angiogenesis. Proc Natl Acad Sci monoclonal antibodies labeled with 90Y: Cancer Res. 2008 Sep;68(17):7090–9. USA. 1999 Dec;96(26):14888–93. a phase I study. Clin Cancer Res. 1999 257. Rodriguez-Manzaneque JC, Lane 267. Nakamura M, Oida Y, Abe Y, Oct;5(10 Suppl):3275s–3280s. TF, Ortega MA, Hynes RO, Lawler J, Yamazaki H, Mukai M, Matsuyama M, 278. Brown MT, Coleman RE, Fried- Iruela-Arispe ML. Thrombospondin-1 et al. Thrombospondin-2 inhibits tu- man AH, Friedman HS, McLendon RE, suppresses spontaneous tumor growth mor cell invasion through the modula- Reiman R, et al. Intrathecal 131I-la- and inhibits activation of matrix metallo- tion of MMP-9 and uPA in pancreatic beled antitenascin monoclonal anti- proteinase-9 and mobilization of vascular cancer cells. Mol Med Rep. 2008 May- body 81C6 treatment of patients with endothelial growth factor. Proc Natl Acad Jun;1(3):423–7. leptomeningeal neoplasms or primary Sci USA. 2001 Oct;98(22):12485–90. 268. Farrow B, Berger DH, Rowley D. brain tumor resection cavities with 258. Hankenson KD, Bornstein P. The Tumor-derived pancreatic stellate cells subarachnoid communication: phase secreted protein thrombospondin 2 is an promote pancreatic cancer cell invasion I trial results. Clin Cancer Res. 1996 autocrine inhibitor of marrow stromal through release of thrombospondin-2. J Jun;2(6):963–72. cell proliferation. J Bone Miner Res. 2002 Surg Res. 2009 Sep;156(1):155–60. 279. Cokgor I, Akabani G, Kuan CT, Mar;17(3):415–25. 269. Bos PD, Zhang XH, Nadal C, Friedman HS, Friedman AH, Coleman 259. Muth CA, Steinl C, Klein G, Lee- Shu W, Gomis RR, Nguyen DX, et al. RE, et al. Phase I trial results of iodine- Thedieck C. Regulation of hematopoietic Genes that mediate breast cancer me- 131-labeled antitenascin monoclonal an- stem cell behavior by the nanostruc- tastasis to the brain. Nature. 2009 tibody 81C6 treatment of patients with tured presentation of extracellular ma- Jun;459(7249):1005–9. newly diagnosed malignant gliomas. J trix components. PLoS One. 2013;8(2): 270. Minn AJ, Gupta GP, Siegel PM, Bos Clin Oncol. 2000 Nov;18(22):3862–72. e54778. PD, Shu W, Giri DD, et al. Genes that me- 280. Reardon DA, Akabani G, Coleman 260. Hankenson KD, Bain SD, Kyriakides diate breast cancer metastasis to lung. RE, Friedman AH, Friedman HS, Hern- TR, Smith EA, Goldstein SA, Bornstein P. Nature. 2005 Jul;436(7050):518–24. don JE 2nd, et al. Phase II trial of murine Increased marrow-derived osteoprogeni- 271. Kang Y, Siegel PM, Shu W, Drobnjak (131)I-labeled antitenascin monoclonal tor cells and endosteal bone formation in M, Kakonen SM, Cordón-Cardo C, et al. antibody 81C6 administered into surgi- mice lacking thrombospondin 2. J Bone A multigenic program mediating breast cally created resection cavities of patients Miner Res. 2000 May;15(5):851–62. cancer metastasis to bone. Cancer Cell. with newly diagnosed malignant gliomas. 261. Hankenson KD, James IE, Apone 2003 Jun;3(6):537–49. J Clin Oncol. 2002 Mar;20(5):1389–97. S, Stroup GB, Blake SM, Liang X, et al. 272. Nakamura-Ishizu A, Suda T. 281. Reardon DA, Quinn JA, Akabani Increased osteoblastogenesis and de- Hematopoietic stem cell niche: an in- G, Coleman RE, Friedman AH, Fried- creased bone resorption protect against terplay among a repertoire of multiple man HS, et al. Novel human IgG2b/mu- ovariectomy-induced bone loss in throm- functional niches. Biochim Biophys Acta. rine chimeric antitenascin monoclonal bospondin-2-null mice. Matrix Biol. 2005 2013 Feb;1830(2):2404–9. antibody construct radiolabeled with Aug;24(5):362–70. 273. Lefevre S, Knedla A, Tennie C, 131I and administered into the surgi- 262. Kyriakides TR, Rojnuckarin P, Reidy Kampmann A, Wunrau C, Dinser R, et al. cally created resection cavity of patients MA, Hankenson KD, Papayannopoulou Synovial fibroblasts spread rheumatoid with malignant glioma: phase I trial re- T, Kaushansky K, et al. Megakaryocytes arthritis to unaffected joints. Nat Med. sults. J Nucl Med. 2006 Jun;47(6):912–8. require thrombospondin-2 for normal 2009 Dec;15(12):1414–20. 282. Schwager K, Kaspar M, Bootz platelet formation and function. Blood. 274. Carlini MJ, De Lorenzo MS, Puricelli F, Marcolongo R, Paresce E, Neri D, 2003 May;101(10):3915–23. L. Cross-talk between tumor cells and et al. Preclinical characterization 263. Kazerounian S, Yee KO, Lawler J. the microenvironment at the metastatic of DEKAVIL (F8-IL10), a novel clin- Thrombospondins in cancer. Cell Mol Life niche. Curr Pharm Biotechnol. 2011 ical-stage immunocytokine which Sci. 2008 Mar;65(5):700–12. Nov;12(11):1900–8. inhibits the progression of collagen- 264. Chijiwa T, Abe Y, Ikoma N, Yamazaki 275. Gueron G, De Siervi A, Vazquez E. induced arthritis. Arthritis Res Ther. H, Tsukamoto H, Suemizu H, et al. Key questions in metastasis: new insights 2009;11(5):R142. Thrombospondin 2 inhibits metastasis in molecular pathways and therapeutic 283. Midwood KS, Williams LV, of human malignant melanoma through implications. Curr Pharm Biotechnol. Schwarzbauer JE. Tissue repair and the microenvironment-modification in NOD/ 2011 Nov;12(11):1867–80. dynamics of the extracellular matrix. SCID/gammaCnull (NOG) mice. Int J 276. Riva P, Arista A, Franceschi G, Frat- Int J Biochem Cell Biol. 2004 Jun;36(6): Oncol. 2009 Jan;34(1):5–13. tarelli M, Sturiale C, Riva N, et al. Local 1031–7.

Licensee OA Publishing London 2013. Creative Commons Attribution License (CC-BY)

For citation purposes: Ruhmann M, Midwood KS. The pro-inflammatory niche: how the extracellular matrix drives