The Role of -Associated Receptor in Osteoimmunology Katharina Nemeth, Michael Schoppet, Nadia Al-Fakhri, Susann Helas, Rolf Jessberger, Lorenz C. Hofbauer and This information is current as Claudia Goettsch of October 1, 2021. J Immunol 2011; 186:13-18; ; doi: 10.4049/jimmunol.1002483 http://www.jimmunol.org/content/186/1/13 Downloaded from

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The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. The Role of Osteoclast-Associated Receptor in Osteoimmunology † ‡ Katharina Nemeth,*x { Michael Schoppet, {Nadia Al-Fakhri,* Susann Helas, Rolf Jessberger, , Lorenz C. Hofbauer,‡, and Claudia Goettsch‡ The term osteoimmunology is coined for molecular clasts are derived from macrophagic/monocytic precursor cells and cellular cross talk between the skeletal and immune and are phenotypically closely related to macrophages and system. Immunomodulatory signals have long been im- dendritic cells (DCs). Cells of the osteoclastic and osteoblastic plicated as key regulators of metabolism. Recently, lineages communicate through cell-to-cell contact and para- osteoclast-associated receptor (OSCAR), an IgG-like re- crine factors in a bidirectional fashion. Osteoclast precursor- ceptor, has been identified as an important osteoimmu- cells express cell surface receptors, including the GM-CSF receptor c-fms, receptor activator of NF-kB (RANK), and nological mediator. OSCAR expression in bone is highly Downloaded from conserved across different species, and the molecule is receptors for costimulatory molecules such as osteoclast- an important costimulatory receptor for osteoclast dif- associated receptor (OSCAR) (3). RANKL is essential for the ferentiation through activation of NFATc1. In humans, differentiation, activation, activity, and survival of OSCAR is expressed by macrophages, monocytes, and (4). The equilibrium and coupling of with bone formation requires fine-tuning mechanisms. Osteoim- monocyte-derived dendritic cells and modulates the re- munology evaluates the mutual effects of the skeletal and the http://www.jimmunol.org/ sponse of the innate and adaptive immune systems by at the molecular and cellular level in both promoting cell activation and maturation, Ag presenta- health and disease. Numerous immunomodulatory signals are tion, and proinflammatory circuits. Human studies indi- concurrently involved in the regulation of bone metabolism cate that OSCAR may contribute to the pathogenesis and and vice versa bone-derived , such as osteopontin, may severity of and rheumatoid . In this have immunomodulatory effects (5). paper, we review the structure-function relationship, ex- With the emerging field of osteoimmunology, it is clear that pression pattern, and physiological role of OSCAR in both the innate and the adaptive immune system are major osteoimmunology and summarize its potential implica- determinants of (6). Within the bone/bone tions for human diseases. The Journal of Immunology, marrow microenvironment, T and B lymphocytes as well as by guest on October 1, 2021 2011, 186: 13–18. mast cells and macrophages provide important signals that affect the coordinated activity of , osteocytes, and one represents a vital organ that protects the brain, the osteoclasts through various pathways (7). Regulatory processes heart and lungs, and the . It is also a become apparent when immune cells are activated during B major storage site for calcium, phosphorus, and pro- acute estrogen withdrawal in postmenopausal bone loss, teins, which are released upon osteoclastic resorption. In addi- during autoimmune diseases such as , or tion, bone is an endocrine organ that produces hormones and in response to oral pathogens in periodontitis (8). Such in- serves as a target organ for paracrine and endocrine factors that ternal or external stimuli often create a proinflammatory cy- control calcium and phosphate homeostasis. The skeleton is tokine milieu that includes RANKL, TNF-a, IL-1 and -6, M- also a complex and dynamic tissue that, in addition to its bio- CSF, and others. This altered microenvironment mechanical properties, harbors stem cells and committed initiates and maintains systemic and/or local bone loss. The precursor cells of the hematopoietic and immune system (1, 2). discovery of RANKL, its receptor RANK, and the soluble Bone mass is determined by the coordinated actions of bone- receptor antagonist (OPG), all of which are resorbing osteoclasts and bone-forming osteoblasts. Osteo involved in these disease processes, has stimulated not only the

*Department of Clinical Chemistry and Molecular Diagnostics and †Department of University Dresden Medical Center, Fetscherstr. 74, D-01307 Dresden, Germany. Internal Medicine and Cardiology, Philipps-University, Marburg; ‡Division of Endo- E-mail address: [email protected] x crinology, Diabetes, and Bone Diseases, Department of Medicine III and Institute of { Abbreviations used in this paper: C, C terminus; DAP12, DNAX-activating of Physiological Chemistry, Technical University Dresden; and Center for Regenerative molecular mass 12 kDa; DC, ; EC, extracellular domain; IC, intracellular Therapies, Dresden, Germany domain; ID, inhibitor of differentiation/DNA binding; KIR, killer Ig-like receptor; Received for publication August 5, 2010. Accepted for publication October 27, 2010. MITF, microphthalmia transcription factor; N, aminoterminus; OPG, osteoprotegerin; OSCAR, osteoclast-associated receptor; Pias3, protein inhibitor of activated Stat3; This work was supported by grants from the Deutsche Forschungsgemeinschaft PPAR-g, peroxisome proliferator-activated receptor-g; R, residue; RANK, receptor (GO1801/4-1 to C.G.; TR67-project B2, HO1875/8-1 to L.C.H.; and JE150/12-1 activator for NF-kB; SP, signal peptide; TM, transmembrane domain; Usf, upstream to R.J.), the MedDrive program of the Medical Faculty of the Technical University stimulatory factor. Dresden (to C.G.), and the von Behring Ro¨ntgen Foundation (to N.A.-F., M.S., and L.C.H.). Copyright Ó 2010 by The American Association of Immunologists, Inc. 0022-1767/10/$16.00 Address correspondence and reprint requests to Dr. Lorenz C. Hofbauer, Division of Endocrinology, Diabetes, and Bone Diseases, Department of Medicine III, Technical www.jimmunol.org/cgi/doi/10.4049/jimmunol.1002483 14 BRIEF REVIEWS: OSCAR IN OSTEOIMMUNOLOGY

field of osteoimmunology, but has also triggered osteoimmu- and inhibition of osteoclastogenesis (19). Deficiency of the nological therapy approaches. ITAM-containing transmembrane signaling adapters, DNAX- More recently, the orphan receptor OSCAR has been im- activating protein of molecular mass 12 kDa (DAP12), or the plicated as a modulator of osteoimmune cell interactions. FcRg results in subtle osteoclastic defects, whereas deletion of OSCAR was initially described by Kim et al. (9), although no both molecules causes severe (20). In summary, naturally occurring ligand has been identified as of today. the bone and immune system employ similar or identical sig- Compared to murine Oscar, whose expression is restricted to naling pathways. osteoclasts (9), human OSCAR is expressed more abundantly by osteoclasts, monocytes, granulocytes, macrophages, and Structure-function relationship of OSCAR monocyte-derived DCs (10). OSCAR has since been charac- Initially, Oscar was identified and characterized in mice (9). terized as a costimulatory regulator of osteoclast differentia- Murine Oscar is localized to 7, adjacent to a tion (9) and modulator of DC maturation and survival (11). region where the paired Ig-like receptors family resides. The In addition, the expression and regulation of OSCAR in the human OSCAR (Mendelian Inheritance in Man 606862) immune system and the skeleton suggests an important func- maps to the leukocyte receptor complex on chromosome tion in the osteoimmune system. In this paper, we review the 19q13.4 (9, 21). This gene locus is close to the gene encoding physiological role of OSCAR and discuss its potential impli- CD85/Ig-like transcript/leukocyte Ig-like receptor and killer cations for the bone:immune interface and the pathogenesis Ig-like receptor (KIR). Common features of these receptors of human diseases. are: 1) the presence of an Ig-like structure; and 2) use of FcRg Downloaded from or DAP12 for signal transduction. Based on its transmem- Osteoclast biology and the role of the immune system brane amino acid sequence, which shares 70% homology with The generation of mature osteoclasts capable of resorbing bone KIR, and the fact that some of the CD85 and KIR molecules is a multistep process that includes commitment of osteoclastic recognize certain MHC class I molecules, OSCAR may have precursor cells, their multinucleation and maturation, and fi- evolved to interact with MHC class I molecules (22), such as

nally activation, which triggers specific cytoskeletal rearrange- classical Ags HLA-A3 and HLA-B27 as well as nonclassical http://www.jimmunol.org/ ments, cell motility, attachment to bone matrix, and resorption. HLA-G1 (23, 24). In addition, distinct collagenolytic enzymes such as cathepsin K The full-length OSCAR cDNA encodes a type I transmem- are required to efficiently degrade bone (12). brane protein of 282 aas and consists of four distinct domains The combination of M-CSF and RANKL is necessary and (Fig. 1). Computerized structure analysis predicts one Ig motif sufficient for in vitro osteoclastogenesis. M-CSF is crucial for (aa 38–121) and one Ig-like motif (aa 135–215). The trans- the proliferation and survival of osteoclastic progenitor cells membrane domain contains an arginine residue that is associ- and binds the receptor c-fms (13, 14). RANKL represents the ated with ITAM-bearing signal transducing adaptor molecules principal regulator for osteoclast differentiation and activation such as FcRg and DAP12 (9). In addition, a transmembrane and promotes survival and motility of osteoclasts (15). When region is predicted that involves the N-terminal aa 1–17 and by guest on October 1, 2021 RANKL binds to RANK expressed on osteoclast precursors, 33–51. The extracellular domain features two potential cyste- a set of transcription factors (NF-kB, AP-1, and NFAT) are ine residues that may stabilize the protein by facilitating di- activated that modulate the expression of osteoclast-specific sulfide bonds. The intracellular domain contains a short effector proteins (12). cytoplasmic tail that is presumably responsible for signal trans- , chemokines, transcription factors, membrane re- duction. Analysis of the suggests a putative ceptors, and costimulatory molecules are induced during im- receptor guanylate cyclase activity, although the functional mune responses and directly or indirectly regulate bone biology relevance has not been demonstrated. Human OSCAR is pres- and skeletal homeostasis. For instance, in a -dependent ent as a monomer with one N-glycosylation site (10). murine arthritis model, inhibition of RANKL by OPG Overall, the structure-function relationship of OSCAR re- prevents both bone and cartilage destruction, but does not mains enigmatic, as its domains and sequence motifs do not affect the inflammatory process (16). In contrast, mice with reveal any activity with certainty and as there are no data on a disrupted Tnfsf11 gene encoding RANKL develop osteopet- the natural ligand or the downstream signaling pathways. It rosis due to the lack of osteoclasts and display defects in lym- is possible that OSCAR may, in fact, represent a cellular decoy phocyte development and lymph node organogenesis (17). receptor. Detection of a soluble OSCAR in serum of patients In fact, targeted deletion of various immunomodulatory (25) could be due to an undefined shedding mechanism of the molecules is also associated with a distinct skeletal phenotype. ectodomain. In addition, protein structure modeling predicts Mice lacking PU.1, a transcription factor that regulates B cell the presence of a signal peptide for human OSCAR, indicat- functions, show a failure in macrophage differentiation (18) ing a secretory function.

FIGURE 1. Structure-function relationship of human OSCAR. Human OSCAR contains two Ig-like motifs and one transmembrane domain, which have one arginine residue (R) associated with ITAM molecules. The extracellular do- main contains one N-glycosylation site and two cysteine residues that contribute to protein stability. C, C terminus; EC,extracellulardomain;IC,intracellular domain;N, amino- terminus; SP, signal peptide; TM, transmembrane domain. The Journal of Immunology 15

Bone DNA binding (IDs), and the protein inhibitor of activated Molecular analysis of the association of murine Oscar with Stat3 (Pias3) inhibit RANKL-induced osteoclastogenesis via ITAM-bearing signal transducing adaptor molecules indicates downregulation of NFATc1 and Oscar (30–32). ID proteins that FcRg is involved in Oscar-mediated signaling. The ex- interact with MITF and attenuate its DNA binding ability to pression of murine Oscar is upregulated in the presence of the E-box of the Oscar promoter (32). The synergistic induction FcRg, but Oscar is weakly expressed on the cell surface in the of Oscar promoter activity by MITF and NFATc1 can be abol- absence of FcRg or DAP12. Therefore, it is likely that Oscar ished by Pias3, which mediates the recruitment of histone deace- is expressed on the cell surface in the absence of adaptor tylases to the promoter regions of NFATc1 and Oscar (31). proteins (22). Although FcRg-deficient mice do not exhibit The peroxisome proliferator-activated receptor-g agonist a defect in osteoclast differentiation (3), the administration KR62776 (33) as well as the flavonoid silibinin (34) concurrently of an Oscar-Ig fusion protein, an Oscar antagonist, inhibits suppress osteoclast differentiation and Oscar expression. In osteoclastogenesis in vitro (9, 26). These data suggest that addition, the MHC class II transactivator CIITA, a downstream FcRg-mediated signal transduction that follows OSCAR ac- target of NFATc1, attenuates RANKL-induced osteoclast for- tivation may not be essential for osteoclast development, but mation through downregulation of NFATc1 and Oscar (35). may be involved in an alternative signaling pathway for osteo- Currently, natural or pharmacological ligands of OSCAR clast differentiation (22). have not been identified. A putative OSCAR ligand is induced The promoter of the murine and human OSCAR on osteoblasts exposed to vitamin D, which also induces RANKL, suggesting a sequential RANKL-OSCAR activation

contains binding sites for transcription factors known to modu- Downloaded from late osteoclastogenesis, including microphthalmia transcription (9). Whether putative OSCAR ligands are membrane-bound factor (MITF), PU.1, and NFATc1 (27) (Fig. 2). Oscar is invol- and require cell–cell contact or whether the ligand is a soluble ved in the positive feedback circuit of the immunoreceptor– protein remains unclear. Identification of an OSCAR ligand NFATc1 pathway by providing costimulatory signals required would expedite the understanding of the osteoimmunological for RANKL-mediated activation of calcium signaling. The acti- implications of OSCAR. Because most of the transcription factors regulating OSCAR gene expression are downstream of vation of NFATc1 is thought to be mediated by the ITAM of http://www.jimmunol.org/ Oscar-associated FcRg (3). How does Oscar interact with the RANKL, a critical -derived differentiation factor for NFATc1 promoter? In fact, chromatin immunoprecipitation osteoclast functions, OSCAR may be involved in the coupling demonstrated that NFATc1 is recruited to the promoter of process between bone resorption and formation. Oscar in RANKL-stimulated osteoclast precursor cells (26, 27). Exposure to the calcineurin inhibitor FK-506 markedly Immune system suppressed murine Oscar expression, indicating that Oscar is Recent studies revealed diverse functions of human OSCAR transcriptionally regulated by NFATc1. In line with these data, in the immune system, including the promotion of cellular there was no Oscar expression in RANKL-stimulated osteo- activation and maturation of immune cells, prevention of clast precursor cells from NFATc1-deficient osteoclasts (26). apoptosis, uptake and presentation of Ags, and enhancement by guest on October 1, 2021 Activated MITF, PU.1 (21), and upstream stimulatory of proinflammatory circuits (10, 11, 36). Thus, OSCAR factors (Usfs) (28) bind to the E-box region (consensus se- modulates the innate and adaptive immune response. quence CACGTG) of the Oscar promoter and cooperate with Most immunological studies of human OSCAR have fo- NFATc1 to modulate Oscar in mice. Notably, activation of cused on its effects on monocytes or monocyte-derived DCs, the RANKL/Mkk6/p38 signaling cascade further enhances which share their precursor cells with osteoclasts (i.e., hemato- transactivation of murine Oscar expression by MITF, PU.1, poietic cells of the myelomonocytic lineage) (37). DCs act as and Usf. Interestingly, IL-1 stimulates osteoclast differentia- potent professional APCs involved in triggering and orches- tion via activation of MITF, a known inducer of Oscar (29). trating adaptive immunity (38–41). Immature DCs constantly In bone, murine Oscar is also modulated by inhibitory loops, screen the surrounding environment for pathogens. DCs and negative regulators of osteoclastogenesis are able to down- endocytose Ag, produce a variety of cytokines, differentiate to regulate Oscar (Table I). For instance, the basic leucin zipper mature DCs, and present pathogen-derived peptides to T cells, transcription factor MafB, the inhibitors of differentiation/ thereby inducing T cell activation. These DC responses are

FIGURE 2. Schematic overview of the murine Oscar promoter. The numbers at top indicate the nucleotide position relative to the transcription initiation site. Modified from Refs. 21 (This research was originally published in The Journal of Biological Chemistry. So, H., J. Rho, D. Jeong, R. Park, D. E. Fisher, M. C. Ostrowski, Y. Choi, and N. Kim. Microphthalmia transcription factor and PU.1 synergistically induce the leukocyte receptor osteoclast-associated receptor gene expression. J. Biol. Chem. 2003; 278:24209–24216. Ó the American Society for Biochemistry and Molecular Biology.), 26 (This research was originally published in The Journal of Biological Chemistry. Kim, Y., K. Sato, M. Asagiri, I. Morita, K. Soma, and H. Takayanagi. Contribution of nuclear factor of activated T cells c1 to the transcriptional control of immunoreceptor osteoclast-associated receptor but not triggering receptor expressed by myeloid cells-2 during osteoclasto- genesis. J. Biol. Chem. 2005; 280:32905–32913. Ó the American Society for Biochemistry and Molecular Biology.), 27 (This research was originally published in The Journal of Biological Chemistry. Kim, K., J. H. Kim, J. Lee, H. M. Jin, S. H. Lee, D. E. Fisher, H. Kook, K. K. Kim, Y. Choi, and N. Kim. Nuclear factor of activated T cells c1 induces osteoclast-associated receptor gene expression during -related activation-induced cytokine-mediated osteoclasto- genesis. J. Biol. Chem. 2005; 280:35209–35216. Ó the American Society for Biochemistry and Molecular Biology.) and updated using MatInspector (Genomatix; marked with *; analysis date October 11, 2010; inspecting sequence GXP_439222; gene identification number 232790). 16 BRIEF REVIEWS: OSCAR IN OSTEOIMMUNOLOGY

Table I. Regulators of OSCAR gene expression in osteoclasts DC maturation (42), OSCAR is apparently expressed indepen- dently of the maturation state on the surface of DCs. As de- Factor Function References scribed above, OSCAR specifically associates with the FcRg, Stimulator RANKL Cytokine 26, 27 which upon phosphorylation of its ITAM motif recruits pro- IL-1 Cytokine 29 tein tyrosine kinases to initiate cellular activation (10, 36). FcRg Signaling adaptor 9, 16, 26, 27 Ligation of human OSCAR triggers intracellular calcium NFATc1 Transcription factor 26, 27 MITF Transcription factor 21 release (10) and is responsible for the sustained secretion of PU.1 Transcription factor 21 high levels of IL-8, high levels of chemokines that attract Th2 USF Transcription factor 28 effectors and regulatory T cells, and lower levels of IL-12p40 Inhibitor MafB Transcription factor 30 PIAS3 Repressor of transcription 31 (11). IL-8 belongs to the CXC family of chemokines with ID Transcription factor 32 various biological functions that include chemotaxis, genera- KR62776 PPAR-g agonist 33 tion of reactive oxygen species, cell adhesion, and promotion Silibinin Polyphenolic flavonoid 34 of angiogenesis (43). IL-8 modulates the function of a variety MHC CIITA Non–DNA-binding 35 coactivator of inflammatory cells, including monocytes (44). Upon human OSCAR ligation on DCs, the expression of PPAR-g, peroxisome proliferator-activated receptor-g. numerous phenotypic markers for cellular activation and maturation, like CD40, CD86, and HLA-DR, is upregulated (11). Moreover, human OSCAR ensures DC survival (11, triggered by recognition of microbial molecules through TLRs, 36). Activation of human OSCAR could rescue DCs that Downloaded from which decipher specific chemical signatures of pathogens. were harvested in the absence of survival factors or the cyto- Whereas TLRs and FcRg are differentially regulated during kine GM-CSF from apoptosis. Activation of the inhibiting http://www.jimmunol.org/ by guest on October 1, 2021

FIGURE 3. Potential effects of OSCAR within the bone, immune, and vascular systems. OSCAR is a costimulatory regulator of osteoclastogenesis. Immune- modulatory effects of OSCAR include promotion of cellular activation via calcium release, maturation of immune cells, prevention of apoptosis through upreg- ulation of Bcl-2, and uptake and presentation of Ags via MHC class II. IL-8–dependent enhancement of proinflammatory circuits is shown for monocytes. Putative vascular functions involve Ag presentation, facilitation of monocyte adhesion, and cell proliferation by endothelial cells. Evidence-based functions are highlighted with persistent lines, and putative functions are shown as dashed lines. The Journal of Immunology 17 receptor CD85j, which is expressed at a similar density on tivity, C-reactive protein serum levels, and the erythrocyte sed- the surface of DCs as OSCAR, abolishes the induction by imentation rate. In this study, TNF-a, a key cytokine and target OSCAR of antiapoptotic proteins Bcl-2 and Bcl-xL (45). in rheumatoid arthritis, was identified as the main inducer Similar to OSCAR, RANKL also has an important role in of OSCAR expression in monocytes. It needs to be clarified DC biology, because RANKL inhibits apoptosis of DCs and whether expression of OSCAR is a bystander effect or whether enhances DC activity (46). Conversely, survival and cytokine it is a consequence of TNF-a induction. Taken together, several production by DCs are inhibited by soluble OPG (47). It will studies implicate OSCAR as a regulator of disease and thus as be interesting to explore combined effects of OSCAR and a potential pharmacological target at the osteoimmunological RANKL on human DC survival. interface. However, as our understanding of OSCAR biology Moreover, human OSCAR is involved in Ag uptake and is still very limited with even the natural ligand remaining presentation in DCs (10), which initiates adaptive immune elusive, intensive research efforts are required to understand response. The role of OSCAR in endocytosis was derived the potential of targeting OSCAR for therapeutic purposes. from its ability to internalize the human anti-OSCAR mAb in DCs. Endocytosis of OSCAR in DCs was observed with ki- Conclusions netics similar to that of the anti-mannose receptor mAb (10). The field of osteoimmunology is rapidly evolving to encompass The receptor complex is then transported to Lamp-1+– and a wide range of molecular and cellular interactions, among HLA-DR+–containing vesicles. These compartments contain them intracellular and cell-to-cell signaling pathways. Detailed receptors that are involved in MHC class II-mediated Ag pre- knowledge of these pathways will provide a scientific basis for sentation. Furthermore, proliferation of naive T cells is syner- future therapeutic approaches to diseases of the immune Downloaded from gistically enhanced by OSCAR after costimulation with TLR system and the skeleton. Research in osteoimmunology may de- ligands (11). lineate new strategies to develop novel therapies for bone loss in Endothelial cells express costimulatory molecules on their sur- inflammatoryandautoimmunediseasesaswellasinosteoporosis. face with positive or negative regulatory effects on T cell responses OSCAR, an IgG-like receptor, has been identified, to our know- (48). Cognate recognition of the endothelium by trafficking ledge, as a new and potentially relevant factor to be studied in the T cells may be critical in initiating the migration and extrava- field of osteoimmunology. OSCAR represents an important http://www.jimmunol.org/ sation of Ag-specific lymphocytes into sites of inflamma- costimulatory receptor for osteoclast differentiation by activa- tion. Endothelial cells also express OSCAR (C. Goettsch, ting NFATc1 and a modulator of the activation and maturation N. Al-Fakhri, M. Schoppet, and L.C. Hofbauer, unpublished of immune cells of the macrophagic/monocytic lineage. Hu- observations); however, the functional role of OSCAR in the man studies indicate that OSCAR may contribute to the vascular system remains to be defined. Established and puta- pathogenesis and severity of diseases at the bone/immune in- tive functions of OSCAR within the skeleton, immune system, terface, including osteoporosis, rheumatoid arthritis, and and vascular system are summarized in Fig. 3. osteolysis adjacent to joint implants. Identification of the

cognate ligand of OSCAR and subsequent signaling pathways by guest on October 1, 2021 OSCAR and human diseases will shed more light onto this molecule and will thus foster Knowledge about the role of OSCAR for human disease is a more detailed and complete understanding of this branch of limited to reports on skeletal and joint disorders. In 2005, Kim regulation of bone metabolism and the immune system. and colleagues (49) identified 10 polymorphisms in the human Disclosures OSCAR gene in a Korean population. One single nucleotide The authors have no financial conflicts of interest. polymorphism (OSCAR-2322A . G) located in the promoter region and the respective specific haplotype (OSCAR-ht1) References were associated with low bone mass and osteoporotic fractures 1. Calvi, L. M., G. B. Adams, K. W. Weibrecht, J. M. Weber, D. P. Olson, in postmenopausal women (49). The authors speculated that M. C. Knight, R. P. Martin, E. Schipani, P. Divieti, F. R. Bringhurst, et al. 2003. the sequences flanking the OSCAR–2322A . G site contain Osteoblastic cells regulate the haematopoietic stem cell niche. Nature 425: 841–846. 2. Arai, F., and T. Suda. 2007. Maintenance of quiescent hematopoietic stem cells in a putative binding site for the transcription factor CREB, the osteoblastic niche. Ann. N. Y. Acad. Sci. 1106: 41–53. which binds to the cAMP response element. Based on this 3. Koga, T., M. Inui, K. Inoue, S. Kim, A. Suematsu, E. Kobayashi, T. Iwata, hypothesis, analysis of OSCAR in osteoclast-specific CREB mu- H. Ohnishi, T. Matozaki, T. Kodama, et al. 2004. Costimulatory signals mediated by the ITAM motif cooperate with RANKL for bone homeostasis. Nature 428: tant mice will be required to elucidate the expression control of 758–763. OSCAR. Moreover, OSCAR was analyzed in patients with 4. Hofbauer, L. C., and M. Schoppet. 2004. Clinical implications of the osteoprotegerin/RANKL/RANK system for bone and vascular diseases. JAMA 292: osteoarthritis as compared with patients with periprosthetic 490–495. osteolysis (50). Synovial fluid of patients with osteoarthritis 5. Weiss, J. M., A. C. Renkl, C. S. Maier, M. Kimmig, L. Liaw, T. Ahrens, S. Kon, induced significantly higher OSCAR and NFATc1 mRNA M. Maeda, H. Hotta, T. Uede, and J. C. Simon. 2001. Osteopontin is involved in the initiation of cutaneous contact hypersensitivity by inducing Langerhans and expression in mouse calvarias bone explants compared with dendritic cell migration to lymph nodes. J. Exp. Med. 194: 1219–1229. periprosthetic osteolysis patients, suggesting that high levels 6. Takayanagi, H., S. Kim, T. Koga, H. Nishina, M. Isshiki, H. Yoshida, A. Saiura, of OSCAR and NFATc1 may facilitate the degenerative pro- M. Isobe, T. Yokochi, J. Inoue, et al. 2002. Induction and activation of the tran- scription factor NFATc1 (NFAT2) integrate RANKL signaling in terminal differ- cess of osteoarthritis. entiation of osteoclasts. Dev. Cell 3: 889–901. A recent study evaluated the role of OSCAR in rheumatoid 7. Walsh, M. C., N. Kim, Y. Kadono, J. Rho, S. Y. Lee, J. Lorenzo, and Y. Choi. 2006. Osteoimmunology: interplay between the immune system and bone metab- arthritis (25). OSCAR was localized on mononuclear cells sur- olism. Annu. Rev. Immunol. 24: 33–63. rounding synovial microvessels and was found to be enhanced in 8. Lorenzo, J., M. Horowitz, and Y. Choi. 2008. Osteoimmunology: interactions of peripheral blood monocytes of patients with rheumatoid ar- the bone and immune system. Endocr. Rev. 29: 403–440. 9. Kim, N., M. Takami, J. Rho, R. Josien, and Y. Choi. 2002. A novel member of the thritis compared with healthy subjects. Moreover, monocytic leukocyte receptor complex regulates osteoclast differentiation. J. Exp. Med. 195: OSCAR expression was positively associated with disease ac- 201–209. 18 BRIEF REVIEWS: OSCAR IN OSTEOIMMUNOLOGY

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