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. at distinct points during wound heal- exert control over a wide range of cell . Conflict of interests: none declared. Conflict of interests: 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 declared in the article 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. 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 differenti- ate 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 . Conflict of interests: none declared. Conflict of interests: 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- declared in the article 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 rheumatoid arthritis? OA Arthritis 2013 Mar 02;1(1):6. 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 3 of 25 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.