New Developments in Osteoimmunology

PERSPECTIVES

OPINION of bone cells on cells of the immune system. In this Perspectives article, I summarize and New developments in osteoimmunology update how the immune system is linked with bone remodelling, focusing on T cells Hiroshi Takayanagi and RANKL in the context of rheumatoid arthritis (RA), and describe advances in the Abstract | Investigations into interactions between the skeletal and immune systems understanding of the osteoblastic HSC niche. were developed during research into arthritis, with characterization of T-cell-mediated regulation of osteoclastogenesis. A new interdisciplinary field—osteoimmunology Immune cell regulation of bone —was created, and has since expanded to encompass disciplines including signal Physiological bone remodelling seems transduction, stem cell niches and fundamental immunology. We have witnessed rapid to occur independently of signalling by progress in understanding the mechanisms of bone damage in arthritis and the roles immune cells, but the ability of the immune of immune molecules in bone, but comparatively less evidence has been provided for system to influence bone metabolism in the role of bone-derived factors in the immune system. Nevertheless, regulation of pathological conditions is being increasingly recognized. Bone destruction in RA, which immune cells, including haematopoietic stem cells, by bone cells is now a hot topic in involves aberrant activation of osteoclasts this field. Here, I discuss recent advances in osteoimmunology and emerging avenues in the absence of equivalent levels of osteo of basic and clinical investigation. blast activity, is the best understood example Takayanagi, H. Nat. Rev. Rheumatol. 8, 684–689 (2012); published online 16 October 2012; of skeletal consequences of autoimmune doi:10.1038/nrrheum.2012.167 inflammation. RANKL is a typical osteo immunological molecule in that it is clearly Introduction signal transduction pathways triggered by essential in both the skeletal and immune sys Historically, bone was thought to be a stable bone-regulating cytokines such as recep tems, and critically mediates the immune cell and metabolically inactive organ with the tor activator of nuclear factor κB ligand regulation of bone.1 Therefore, I discuss here sole function of supporting the locomotive (RANKL; also known as TNF ligand super the pathogenesis of bone destruction in RA activity of the body. However, bone marrow family member 11) have indicated that the by focusing on type 17 T helper (TH17) cells has long been known, alongside the thymus, immune and bone systems share a huge and RANKL; nevertheless, these mecha as a primary lymphoid organ.1,2 Thus, the range of regulatory mechanisms in terms of nisms of immune cell-mediated regulation of immune function of bone has been well cellular signalling pathways.1,4 bone might be applied to various pathologi recognized, but detailed studies of how bone Increasing evidence suggests that not only cal conditions, including spondyloarthritis, tissue contributes to immune responses were does the immune system influence bone, systemic lupus erythematosus, periodontitis nevertheless neglected for a long time. The but also that bone reciprocally regulates the and bone cancer. difficulty of accessing hard bone tissue—now immune system. Molecular mechanisms of less of a problem with modern techniques bone-mediated regulation of the immune Osteoclast activation in RA by RANKL —hampered molecular analysis and probably system are being elucidated, particularly in RA is an autoimmune disease that is charac contributed to this delayed characterization. relation to how osteoblasts, osteoprogenitor terized by inflammation of the synovial joint, The past decade has, however, witnessed cells and other nearby cells comprise a leading to severe structural damage includ surprisingly rapid progress in osteoimmuno haematopoietic stem cell (HSC) niche that ing bone destruction. Investigations into the logy, a discipline that examines the inter contributes to immune regulation.5,6 Indeed, sites of bone destruction in patients with actions and shared mechanisms between the in the bone marrow microenvironment, RA and animal models of the disease have skeletal and immune systems.1,3 bone and immune cells are localized side suggested that osteoclasts (bone-resorbing Research into the mechanisms of bone by side and any resident cell can be influ cells) have a substantial role in RA patho destruction in autoimmune arthritis has enced by surrounding cells of either bone genesis.7 The osteoclast differentiation fac inevitably led investigators to study inter or immune lineage.5,6 Thus, functions of tor, RANKL, is highly expressed in the RA actions between cells of the immune and the immune and skeletal systems should synovium, and inflammation-mediated bone skeletal systems. Advances in genetic now be reconsidered in the context of the damage is largely attributable to abnormally engineering have revealed unexpected osteoimmune system as a whole. high expression of RANKL.1,7 skeletal phenotypes in mice deficient in In 2009, when I reviewed osteoimmuno immune molecules, such as osteoporotic logy in the context of rheumatic disease in Cell sources of RANKL in RA and osteopetrotic phenotypes (Table 1).1 this journal,7 research had focused on how the With the destructive role of RANKL estab Furthermore, studies of the intracellular immune system, via osteoclastogenic T cells, lished, the next question to arise was that of mediates bone destruction. Just 3 years later, how autoimmune reactions induce RANKL Competing interests understanding of osteoimmunology has expression and subsequent osteoclasto The author declares no competing interests. broadened to encompass the reciprocal effect genesis. RANKL expression can be detected

in both synovial fibroblasts and T cells in the Table 1 | Skeletal phenotypes caused by deficiencies in immunomodulatory molecules in mice 7 inflamed joints of patients with RA. As I dis Targeted gene*‡ Protein product Skeletal phenotype effects of gene knockout*‡ cussed in 2009,7 T‑cell derived RANKL was initially proposed to be the main contribu Bone Rate of bone Rate of bone volume resorption formation tor to enhanced osteoclastogenesis in RA, but T cells also produce anti-osteoclastogenic Cytokines, secreted proteins, receptors and channels cytokines, such as interferon (IFN)‑γ, which S1pr1§ Sphingosine‑1-phosphate Decreased Increased ND counterbalance the action of RANKL.8 Thus, receptor 1 it is not easy for T cells to exert a positive S1pr2 Sphingosine‑1-phosphate Increased Decreased Unchanged effect on osteoclastogenesis. In fact, if acti receptor 2 vated T cells are co-cultured with osteoclast Cd200 CD200 molecule Increased Decreased Unchanged (males); precursor cells, the T cells actually inhibit decreased (females) osteoclastogenesis rather than increase Ccr2 CC-chemokine receptor 2 Increased Decreased Unchanged it.8 By contrast, synovial fibroblasts have a Osmr Oncostatin‑M-specific Increased Decreased Decreased potent ability to induce osteoclastogenesis receptor subunit β in cell culture. Therefore, it seems likely that Trpv4 Transient receptor potential Increased Decreased Unchanged synovial cell RANKL is the major driver of cation channel subfamily V osteoclastogenesis in the synovium, and that member 4 T cells, although certainly contributing, do Ptprc Receptor-type tyrosine- Increased Decreased Decreased so indirectly.1,7 protein phosphatase C (also known as CD45) Traditionally, T‑helper (TH) cells were Intracellular adaptor and signalling molecules classed as either type 1 or type 2 (TH1 or TH2) on the basis of the cytokines they produced. Cyld Ubiquitin carboxyl-terminal Decreased Increased Unchanged hydrolase CYLD Nevertheless, as TH1 and TH2 cells inhibit osteoclastogenesis through the production, Sh3bp2 SH3 domain-binding Decreased Decreased Decreased respectively, of IFN‑γ and IL‑4, it was neces protein 2 Hcst Haematopoietic cell signal Increased Decreased Unchanged sary to identify a different TH-cell subset, one with the ability to increase osteoclastogen transducer (also known as DAP10) 1 esis. In the course of these efforts, TH17 cells were shown, exclusively among T-cell Transcription factors subsets, to have the capacity to induce osteo Zbtb7a (early phase Zinc finger and BTB domain- Decreased Increased Unchanged clastogenesis. Interestingly, even T 17 cells of osteoclast containing protein 7A (also H development)|| known as LRF) do not induce osteoclastogenesis through Zbtb7a (late phase Zinc finger and BTB Increased Decreased Unchanged their own expression of RANKL, but instead of osteoclast domain-containing do so indirectly, via the IL‑17-mediated development)¶ protein 7A induction of RANKL expression on syno Prdm1¶ PR domain containing 1, Increased Decreased Decreased vial fibroblasts. In addition, TH17 cells with ZNF domain (also promote local inflammation, causing exag known as Blimp1) gerated expression of TNF, IL‑6 and IL‑1, Bcl6 B-cell lymphoma 6 protein Decreased Increased Decreased all of which increase RANKL expression on homolog synovial fibroblasts and activate osteoclast Irf8 Interferon regulatory factor 8 Decreased Increased Increased 7 precursor cells (Figure 1). Maf Transcription factor Maf Decreased Decreased Decreased Although accumulating evidence indicates *For the details of the primary literature please refer to Supplementary reference list (Supplementary Table 1 online). ‡All § that TH1 cells are not an osteoclastogenic experimental animals were generated by conventional gene knockout unless otherwise indicated. Conditional knockout 7 (CD11b-Cre, Cre transgene becomes active in CD11b positive myeloid cells). ||Conditional knockout (Mx1-Cre, Cre transgene T‑cell subset, targeted depletion of TH1 and becomes active in various cell types, including immature hematopoietic cells upon poly I:C treatment). ¶Conditional knockout (Ctck-Cre, Cre transgene becomes active in osteoclasts). Abbreviations: Blimp1, B lymphocyte-induced maturation protein 1; TH17 cells expressing lymphotoxin‑α was shown to suppress inflammation and bone DAP10, DNAX-activation protein 10; LRF, leukaemia/lymphoma-related factor; ND; not determined. destruction in mice with collagen-induced 9 arthritis; thus, whereas TH17 cells seem to be Targeting RANKL in arthritis seems to be powerful tool in the detailed analysis of cellu 11,12 much more important than the TH1 subset in a promising method to specifically prevent lar sources of human RANKL. Potentially, the context of osteoclastogenesis in RA, the bone damage,10 although the anti-RANKL targeting RANKL in bone pathology may role of TH1 cells in autoimmune inflammation antibody denosumab has minimal effects have unexpected immune consequences, as nevertheless warrants further investigation. on cartilage damage or joint-space narrow I discuss in the section Immune functions of ing (Box 1).10 T‑cell-specific knockout of RANKL, later.

Targeting RANKL and TH17 cytokines Rankl in mice has shown that T‑cell derived

Considering the exclusive role of TH17 cells Rankl does not contribute to physiological B-cell RANKL effects on bone 11 in RA osteoclastogenesis, targeting TH17- bone regulation, but its role in pathological The therapeutic effect of anti-CD20 anti related cytokines, IL‑6, IL‑23, IL‑17A, IL‑21 settings such as autoimmune arthritis is an body has highlighted the role of B cells in the and IL‑22 might be an auspicious strategy intriguing issue to address in the near future. pathogenesis of arthritis.13 Data from a study against inflammation-associated bone loss. Rankl conditional knockout mice will be a in ovariectomized mice available have now

Initiation signalling factor in bone that also signals in Macrophages, DCs Genetic factors the immune system. Autoantigen? Environmental factors Immune functions of RANKL As discussed above, RANKL expressed by synovial fibroblasts drives bone destruction

Cartilage TH0 TGF-β, IL-6, TH17 B cells in RA via stimulation of osteoclastogenesis. IL-23 Pannus IL-17 It has been suggested that osteoblastic cells or bone marrow stromal cells express RANKL CCL20 to regulate bone remodelling. In adult mice, Migration Autoantibodies Complement however, osteocyte-specific knockout of Rankl has shown that osteocytes are the crit ical source of Rankl in physiological bone T 17 B cells H remodelling in mice.11,14 Thus, the cell-type Bone Macrophages, specific function of RANKL in bone has mast cells, Osteoclast neutrophils begun to be understood. What about the role precursors IL-17 IL-17 of RANKL in the immune system? RANKL Synovial IFN- broblasts was originally suggested to have a role in the γ IL-6, IL-7 TH1 activation of dendritic cells by T cells, but IL-4 RANKL also has a role in the regulation of TH2 RANKL 7 regulatory T (TREG) cells, as discussed next.

TREG TNF, IL-1, IL-6 In a mouse model of diabetes, admini + + Osteoclasts stration of CD4 CD25 TREG cells prevented destruction of β cells in the islets of Langerhan. This effect was mediated by preferential

Bone destruction Inammation accumulation of TREG cells in pancreatic lymph nodes and islets, where they inhibited + Figure 1 | Mechanisms of bone destruction in autoimmune arthritis. A variety of cell populations, development of CD8 T cells into cytotoxic including T cells, B cells, innate immune cells, synovial fibroblasts and osteoclasts have roles in T cells. Inhibition of the RANKL–RANK the development of autoimmune arthritis. TH17 cells contribute to the development of arthritis interaction prevented the accumulation of in the initiation and inflammatory phases of disease, through production of autoantibodies as well T cellsin the pancreaticislets, resulting in as activation of innate immunity. Importantly, synovial fibroblasts contribute to T 17-cell-mediated REG H destruction of β cells by cytotoxic T cells.15 immunity in the inflammatory phase by promoting T 17-cell migration to the inflamed joint, H Similarly, inhibition of RANKL affected the followed by TH17-cell proliferation with an increase in IL‑17 production. TH17 cells, exclusively expansion of TREG cells in the intestine of among T‑cell subsets, are osteoclastogenic. TH17 cells secrete relatively large amounts of IL‑17, which induces expression of RANKL, but not IFN‑γ, on synovial fibroblasts. IL‑17 stimulates local colitic mice thus worsening inflammation inflammation resulting in the production of proinflammatory cytokines such as TNF, IL‑1 and IL‑6 by in the gut16. Furthermore, Langerhan cells of synovial macrophages. These cytokines further enhance RANKL expression on synovial fibroblasts K14-Rankl transgenic mice, in which Rankl is and act on osteoclast precursor cells. RANKL expression on T 17 cells might partly contribute to H overexpressed in the skin, elevated numbers + the enhanced osteoclastogenesis induced by these cells. Thus, the interaction of infiltrating CD4 of T cells in the spleen.17 Peripheral expan T cells with the synovium in joints has an essential role in the pathogenesis of rheumatoid arthritis REG sion of T cell numbers was demonstrated to in terms of both inflammation and bone destruction. Abbreviations: CCL20, CC chemokine REG ligand 20; DC, dendritic cell; MMP, matrix metalloproteinase; RANKL, receptor activator of nuclear be dependent on Langerhan cells, with deple tion of the latter substantially reducing the factor κB ligand; TH0, naive T cell; TH1, type 1 T helper (cell); TH2, type 2 T helper (cell); TH17, 17 type 17 T helper (cell); TREG, regulatory T (cell). peripheral pool of TREG cells. In humans and mice with breast cancer, RANKL expressed suggested a direct role of RANKL expression as I have mentioned, with analysis of the by T cells in the tumour has been associated by B cells in the regulation of bone metabo functions of known immune molecules in with metastatic activity.18 RANKL on T cells is lism.12 T‑cell specific knockout of Rankl in the skeletal system. In this regard, much has also critical for the development of the thymic the mice did not alter ovariectomy-induced been learned from skeletal phenotypes of medullary epithelial cells which are respon bone loss, but mice lacking Rankl protein mice deficient in various immunomodula sible for the negative selection of self-reactive expression in their B cells were partially tory molecules (Table 1), though equivalent T cells.19–21 Therefore, RANKL can be both a protected from the bone loss via attenuated deficiencies have—mostly—not yet been stimulator and a suppressor of immune res osteoclastogenesis.12 The role of B cells in reported in people. Although less is known ponses, depending on the context, and the promoting pathogenic osteoclastogenesis about functions in the immune system of detailed implications for rheumatic diseases should be analyzed in other models of bone signalling molecules released by bone cells, are not yet known. pathology in future. accumulating evidence of immune pheno types in mice and humans deficient in bone- Implications of targeting RANKL Molecular bone–immune crosstalk regulatory molecules (Table 2) indicates that As I have mentioned, the anti-RANKL anti Shared signalling pathways reciprocal regulation of the immune system body denosumab is in clinical trials and/or Studies of the signalling molecules shared by the skeletal system occurs. RANKL use for various bone pathologies (Box 1). by the immune and skeletal systems began, exemplifies a molecule identified as a Given the extensive functions of RANKL

686 | NOVEMBER 2012 | VOLUME 8 www.nature.com/nrrheum © 2012 Macmillan Publishers Limited. All rights reserved BONE RESEARCH outside of the skeletal system, careful inves Box 1 | Denosumab and bone pathology tigation will be required to guard against Denosumab is a fully humanized anti-RANKL antibody that inhibits the RANKL–RANK interaction, unexpected adverse effects of denosumab. It is thus potently suppressing osteoclast formation and function, and which has been approved worth noting, however, that serious immuno by the US FDA for the treatment of osteoporosis and skeletal complications associated with logic problems have not been encountered in bone metastases in cancer.22 Denosmab reportedly has therapeutic effects on bone damage clinical trials of the antibody to date.22 (as measured using the Sharp score) in patients with RA in clinical trials, but not on cartilage degradation (as measured by joint-space narrowing).10 Possibly for this reason, denosumab has Immunomodulation by bone cells not been approved for in the US for the treatment of RA; nevertheless, the possibility remains that it might be approved in other countries, such as Japan, if the effects on bone are carefully The role of bone marrow evaluated. Although RANKL has various functions in the immune and other biological systems, Bone marrow is a primary lymphoid organs, to date no serious adverse effects reported in clinical trials of denosumab.22 harbouring HSCs, memory B cells and other Abbreviations: RA, rheumatoid arthritis; RANK, receptor activator of nuclear factor κB (also known as TNF B‑lineage cells.23 These haematopoietic cells receptor superfamily member 11A); RANKL, RANK ligand (also known as TNF ligand superfamily member 11). share their microenvironment with bone cells including osteoblasts, osteoclasts and possibly even osteocytes. Therefore, it is Table 2 | Immunological phenotypes caused by deficiencies in bone-regulatory molecules* not surprising that bone cells, traditionally Targeted gene Protein product Immunological phenotype (mouse, human) thought to be involved only in bone metabo Knockout mouse‡ Humans lism, participate in regulation of the immune Cytokines and secreted signalling molecules system. Principally, this regulation relates to control of haematopoiesis—and, therefore, Sost, SOST Sclerostin Fewer B cells (bone marrow) NA of the cellular composition of the immune Spp1, SPP1 OPN Fewer NKT cells (liver and Decreased IFN‑α production system—by regulation of the HSC niche, the spleen, not thymus) by pDCs bone-marrow microenvironment in which Acp5, ACP5 Tartrate-resistant ND Spondyloenchondrodysplasia, HSC fate is controlled, by bone cells. In this acid phosphatase increased levels of OPN type 5 and IFN‑ section I discuss evidence for the influence α of osteoblasts, osteoclasts and other poten Ctsk, CTSK Cathepsin K No difference in frequency of NA the onset of experimental tial cellular components of the HSC niche on autoimmune encephalomyelitis, HSC function. but decreased the severity of the paralytic symptoms Osteoblasts and the HSC niche Tnfrsf11a, RANK Decreased development Hypergammaglobulinaemia, Groundbreaking research has suggested TNFRSF11A of mTEC fewer B cells that osteoblasts are components of the Tnfsf11, TNFSF11 RANKL Decreased development NA HSC niche.24,25 These studies were based on of mTEC genetically modified mouse models in which Tnfrsf11b, OPG Increased development NA osteoblast numbers were increased. In one TNFRSF11B of mTEC study, Calvi et al.24 used mice expressing Intracellular signalling molecules constitutively active parathyroid hormone/ Vhl, VHL Von Hippel-Lindau Increased expression of NA parathyroid hormone-related peptide recep disease tumour erythropoietin and increased § tor (PPR) in osteoblastic cells. The activation suppressor erythropoiesis of PPRs in osteoblasts not only induced an *As relevant to rheumatic diseases; for details of the primary literature please refer to Supplementary reference list (Supplementary Table 2 online). ‡All experimental animals were generated by conventional gene knockout unless otherwise increase in osteoblast number but also upreg indicated. §Conditional knockout (Osx-Cre, Cre transgene becomes active in late-proliferating chondrocytes and in osteoblastic lineage cells). Abbreviations; mTEC, medullary thymic epithelial cell; NA, not applicable; ND not determined; ulated expression of the Notch ligand protein NKT, natural killer T cells; OPG, osteoprotegerin (also known as TNF receptor superfamily member 11B); OPN, osteopontin jagged‑1 (Jag1) in osteoblasts.24 This study (also known as bone sialoprotein 1); pDC, plasmacytoid dendritic cell; RANK, receptor activator of nuclear factor κB (also known as TNF receptor superfamily member 11A); RANKL, RANK ligand (also known as TNF ligand superfamily member 11). thus implicated Notch signalling in increasing HSC numbers. In contrast to these findings, however, others have reported that Jag1 and is critical for sustaining production of all can be considered to constitute an endosteal Notch signalling are dispensable for the main mature blood cells and a normal HSC pool HSC niche. However, subsequent reports tenance of HSC populations.23 For example, size. Angiopoietin‑1 produced by osteoblasts have suggested that additional cell types Notch signalling is not necessary for HSC activates angiopoietin‑1 receptor on HSCs contribute to the HSC niche (Figure 2). The maintenance at steady state and under and promotes tight adhesion of these cells vascular niche, which is largely populated certain situations of myeloablative injury.23 to the niche, resulting in HSC quiescence.26 by endothelial cells and perivascular cells, Therefore, the role of Notch signalling in the However, the physiological significance of contributes to haematopoiesis by express maintenance of HSC remains controversial. these findings has been questioned in sub ing factors that promote this process. Kit Another study to support the concept sequent studies that have shown that HSC ligand, also known as stem cell factor (SCF), of an osteoblastic HSC niche reported that number does not necessarily correlate with is one such factor and is mainly produced angiopoietin‑1 expressed in osteoblasts osteoblast number.27,28 by leptin receptor-expressing perivascular regulates HSC maintenance.26 Most HSCs stromal cells.29 In addition, areas adjacent in adult bone marrow are in the G0 phase Other cells constituting the HSC niche to blood vessels are thought to constitute of the cell cycle (quiescence). A balance As mentioned above, osteoblasts seem to be an HSC niche.23 In 2010, CXC-chemokine between HSC quiescence and activation involved in regulation of HSC pool size and ligand 12 (CXCL12)-abundant reticular

Nestin+ Adipocytes to participate in the osteoimmune system. MSCs Autonomic It has been demonstrated that targeted dis nerve with Lepr+ Schwann cells ruption of sclerostin results in a decreased perivascular stromal cells number of B cells due to elevated B‑cell apop CAR tosis.40 As sclerostin is primarily expressed cells in osteocytes and is not expressed in any haematopoietic lineages, the B‑cell defect in these mice was caused by the impaired pro Osteoblasts duction of sclerostin by osteocytes.40 These

HSCs results suggest a novel role of osteocytes in the regulation of bone marrow environments that support immunological cells. Vascular sinus ? Osteoimmunological communication All cells in bone tissue undergo intensive Endothelial cells ? communication to maintain mechanical

OsteocytesOsteocytes stability, calcium homeostasis and haemato Osteoclasts poiesis in the skeletal system. Efforts are Bone marrow niche ongoing to identify molecules that mediate Vascular niche Reticular niche Endosteal niche communication between cells in bone, and the involvement of several immuno Figure 2 | HSC maintenance in the bone marrow. The bone marrow provides microenvironmental logical mediators in this crosstalk has been niches that support the self-renewal ability, multipotency and quiescence of HSCs. Three types of shown. Osteoprotegerin (also known as TNF HSC niches, endosteal (containing osteoblasts), vascular (containing Lepr+ perivascular stromal cells) and reticular (containing CAR cells) have been reported in mice, which mainly regulate the receptor superfamily member 11B), a decoy HSC pool size, stem cell factor production and HSC retention, respectively.24,29,30 Nestin+ MSCs receptor for RANKL, and RANKL are among and nonmyelinating Schwann cells are also suggested to be involved in HSC maintenance. CAR the first such molecules to be identified; they cells and nestin+ MSCs have the capacity to differentiate into osteoblasts and adipocytes.30,32 are expressed by osteoblasts and regulate Nonmyelinating Schwann cells maintain HSC quiescence by regulating activation of latent osteoclastogenesis.1 Stimulation of bone 31 transforming growth factor β. The role of osteoclasts in the regulation of HSC mobilization formation after bone resorption is partly 33,34 remains controversial. Abbreviations: CAR, CXC chemokine ligand 12-abundant reticular induced by classical coupling factors, such (cell); HSC, haematopoietic stem cell; Lepr, leptin receptor; MSC, mesenchymal stem cell. as insulin-like growth factor41 and TGF‑β42 which, besides these skeletal roles, are also (CAR) cells, which are localized in closer regulation of HSC mobilization by modify considered to be immunological molecules. proximity to vessels than osteoblasts, were ing the HSC niche,33,34 as well as having Much has been done to identify molecules proposed to be the cells that formed the immunomodulatory roles in plasma cell other than these classic factors that link bone reticular niche. As CAR cells in mouse bone maintenance35 and antigen presentation.36 resorption to formation, although in vivo marrow have the capacity to differenti Further studies are absolutely required for evidence remains scarce.41,42 Ephrin‑B2 and ate into osteoblasts and adipocytes in vitro the detailed understanding of the immune ephrin B4, for example, are known to help and in vivo, it is possible that CAR cells regulation by bone cells. mediate the transition of bone resorption are also involved in the endosteal niche as to formation.43 Furthermore, since 2011 osteoprogenitor cells.30 Further studies have Other topics semaphorins have emerged as potent media implicated other cell types in regulating dif Bone marrow oedema, which may be at tors of bone cell communication. Osteoclast ferent stages of HSC maintenance (Figure 2). least partly attributable to TNF-mediated semaphorin 4D, for example, maintains the Nonmyelinating Schwann cells maintain haematopoiesis, has emerged as an MRI- bone resorption phase of bone remodelling HSC quiescence by regulating activation of based biomarker of inflammatory arthritis.37 by inhibiting osteoblastic bone formation in latent TGF‑β.31 Nestin+ mesencymal stem As alteration of the bone marrow micro mice.44 As Sema4D is known to regulate the cells (MSCs) express HSC maintenance environment by TNF might be involved in an activation of B cells and dendritic cells and genes, such as those encoding CXCL12 and increase in the circulating osteoclast precur inhibits monocyte migration, this molecule angiopoietin‑1.32 sor number,38,39 this lesion is a novel example can be considered as an osteoimmunological Thus each of the many cell types described of inflammation-mediated regulation of mediator. Semaphorin 3A, by contrast, not above interacts with HSCs in bone marrow. osteoclastogenesis through ectopic haemato only inhibits bone resorption in mice but also More evidence is required to clearly deter poiesis. Studies of bone marrow oedema enhances bone formation, suggesting that it mine the relative contribution of bone cells might provide insights into the relationship could be a powerful bone-protecting factor.45 to the regulation of haematopoiesis. between inflammation, osteoclastogenesis and haematopoiesis. Conclusions The role of osteoclasts Osteoimmunology began with study of the Less evidence has been obtained for the role Future perspectives mechanisms of bone pathology in arthritis, of osteoclasts in the regulation of the immune The role of osteocytes and these investigations have continued to system than for osteoblasts, but reports In addition to cells within bone marrow, bone drive advances in this field. RANKL is the suggest that osteoclasts participate in the matrix-embedded cells—osteocytes—seem most important and well studied molecule

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