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Updating osteoimmunology: regulation of bone cells by innate and adaptive immunity

Nature Reviews Rheumatology volume 14, pages 146–156 (2018)Cite this article

Subjects

Key Points

  • Multiple elements of the adaptive immune system, including B cells and T cells, contribute to autoimmunity-associated bone pathology

  • Commensal microbiota can affect bone through involvement in immune responses at sites proximal and distal to bone

  • Various innate immune triggers such as nucleotides can lead to pathologic bone loss

  • Bone cells actively regulate immune cell maintenance and acute immune responses

  • Tissue-specific receptor activator of nuclear factor-κB ligand (RANKL) exerts unique effects on bone and the immune system

Abstract

Osteoimmunology encompasses all aspects of the cross-regulation of bone and the immune system, including various cell types, signalling pathways, cytokines and chemokines, under both homeostatic and pathogenic conditions. A number of key areas are of increasing interest and relevance to osteoimmunology researchers. Although rheumatoid arthritis has long been recognized as one of the most common autoimmune diseases to affect bone integrity, researchers have focused increased attention on understanding how molecular triggers and innate signalling pathways (such as Toll-like receptors and purinergic signalling pathways) related to pathogenic and/or commensal microbiota are relevant to bone biology and rheumatic diseases. Additionally, although most discussions relating to osteoimmune regulation of homeostasis and disease have focused on the effects of adaptive immune responses on bone, evidence exists of the regulation of immune cells by bone cells, a concept that is consistent with the established role of the bone marrow in the development and homeostasis of the immune system. The active regulation of immune cells by bone cells is an interesting emerging component of investigations that seek to understand how to control immune-associated diseases of the bone and joints.

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Figure 1: Immune regulation of bone destruction in rheumatoid arthritis (RA).
Figure 2: Microbiota and osteoimmunology.
Figure 3: Purinergic signalling regulates bone cells and inflammation.
Figure 4: Interaction between immune cells and bone cells in homeostasis and sepsis.
Figure 5: The effects of tissue-specific RANKL on bone and the immune system.

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References

  1. Arron, J. R. & Choi, Y. Bone versus immune system. Nature 408, 535–536 (2000).

    CAS  PubMed  Google Scholar 

  2. Walsh, M. C. et al. Osteoimmunology: interplay between the immune system and bone metabolism. Annu. Rev. Immunol. 24, 33–63 (2006).

    CAS  PubMed  Google Scholar 

  3. Yu, V. W. & Scadden, D. T. Hematopoietic stem cell and its bone marrow niche. Curr. Top. Dev. Biol. 118, 21–44 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  4. Ash, P., Loutit, J. F. & Townsend, K. M. Osteoclasts derived from haematopoietic stem cells. Nature 283, 669–670 (1980).

    CAS  PubMed  Google Scholar 

  5. Walsh, M. C. & Choi, Y. Biology of the RANKL-RANK-OPG system in immunity, bone, and beyond. Front. Immunol. 5, 511 (2014).

    PubMed  PubMed Central  Google Scholar 

  6. Takayanagi, H. New developments in osteoimmunology. Nat. Rev. Rheumatol. 8, 684–689 (2012).

    CAS  PubMed  Google Scholar 

  7. Fuller, K., Wong, B., Fox, S., Choi, Y. & Chambers, T. J. TRANCE is necessary and sufficient for osteoblast-mediated activation of bone resorption in osteoclasts. J. Exp. Med. 188, 997–1001 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  8. Kong, Y. Y. et al. OPGL is a key regulator of osteoclastogenesis, lymphocyte development and lymph-node organogenesis. Nature 397, 315–323 (1999).

    CAS  PubMed  Google Scholar 

  9. Lacey, D. L. et al. Osteoprotegerin ligand is a cytokine that regulates osteoclast differentiation and activation. Cell 93, 165–176 (1998).

    CAS  PubMed  Google Scholar 

  10. Simonet, W. S. et al. Osteoprotegerin: a novel secreted protein involved in the regulation of bone density. Cell 89, 309–319 (1997).

    CAS  PubMed  Google Scholar 

  11. Yasuda, H. et al. Osteoclast differentiation factor is a ligand for osteoprotegerin/osteoclastogenesis-inhibitory factor and is identical to TRANCE/RANKL. Proc. Natl Acad. Sci. USA 95, 3597–3602 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  12. Kostenuik, P. J. Osteoprotegerin and RANKL regulate bone resorption, density, geometry and strength. Curr. Opin. Pharmacol. 5, 618–625 (2005).

    CAS  PubMed  Google Scholar 

  13. Gul, G., Sendur, M. A., Aksoy, S., Sever, A. R. & Altundag, K. A comprehensive review of denosumab for bone metastasis in patients with solid tumors. Curr. Med. Res. Opin. 32, 133–145 (2016).

    CAS  PubMed  Google Scholar 

  14. Zaheer, S., LeBoff, M. & Lewiecki, E. M. Denosumab for the treatment of osteoporosis. Expert Opin. Drug Metab. Toxicol. 11, 461–470 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  15. Boleto, G., Drame, M., Lambrecht, I., Eschard, J. P. & Salmon, J. H. Disease-modifying anti-rheumatic drug effect of denosumab on radiographic progression in rheumatoid arthritis: a systematic review of the literature. Clin. Rheumatol. 36, 1699–1706 (2017).

    PubMed  Google Scholar 

  16. Crotti, T. N., Dharmapatni, A. A., Alias, E. & Haynes, D. R. Osteoimmunology: major and costimulatory pathway expression associated with chronic inflammatory induced bone loss. J. Immunol. Res. 2015, 281287 (2015).

    PubMed  PubMed Central  Google Scholar 

  17. Ginaldi, L. & De Martinis, M. Osteoimmunology and beyond. Curr. Med. Chem. 23, 3754–3774 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  18. Jones, D., Glimcher, L. H. & Aliprantis, A. O. Osteoimmunology at the nexus of arthritis, osteoporosis, cancer, and infection. J. Clin. Invest. 121, 2534–2542 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  19. Komatsu, N. & Takayanagi, H. Inflammation and bone destruction in arthritis: synergistic activity of immune and mesenchymal cells in joints. Front. Immunol. 3, 77 (2012).

    PubMed  PubMed Central  Google Scholar 

  20. Catrina, A. I., Svensson, C. I., Malmstrom, V., Schett, G. & Klareskog, L. Mechanisms leading from systemic autoimmunity to joint-specific disease in rheumatoid arthritis. Nat. Rev. Rheumatol. 13, 79–86 (2017).

    CAS  PubMed  Google Scholar 

  21. Komatsu, N. & Takayanagi, H. Arthritogenic T cells in autoimmune arthritis. Int. J. Biochem. Cell Biol. 58, 92–96 (2015).

    CAS  PubMed  Google Scholar 

  22. Gravallese, E. M. et al. Synovial tissue in rheumatoid arthritis is a source of osteoclast differentiation factor. Arthritis Rheum. 43, 250–258 (2000).

    CAS  PubMed  Google Scholar 

  23. Kong, Y. Y. et al. Activated T cells regulate bone loss and joint destruction in adjuvant arthritis through osteoprotegerin ligand. Nature 402, 304–309 (1999).

    CAS  PubMed  Google Scholar 

  24. Takayanagi, H. et al. Involvement of receptor activator of nuclear factor κB ligand/osteoclast differentiation factor in osteoclastogenesis from synoviocytes in rheumatoid arthritis. Arthritis Rheum. 43, 259–269 (2000).

    CAS  PubMed  Google Scholar 

  25. Tunyogi-Csapo, M. et al. Cytokine-controlled RANKL and osteoprotegerin expression by human and mouse synovial fibroblasts: fibroblast-mediated pathologic bone resorption. Arthritis Rheum. 58, 2397–2408 (2008).

    CAS  PubMed  Google Scholar 

  26. Horwood, N. J. et al. Activated T lymphocytes support osteoclast formation in vitro. Biochem. Biophys. Res. Commun. 265, 144–150 (1999).

    CAS  PubMed  Google Scholar 

  27. Rudd, C. E. & Raab, M. Independent CD28 signaling via VAV and SLP-76: a model for in trans costimulation. Immunol. Rev. 192, 32–41 (2003).

    CAS  PubMed  Google Scholar 

  28. Takayanagi, H. et al. T-cell-mediated regulation of osteoclastogenesis by signalling cross-talk between RANKL and IFN-γ. Nature 408, 600–605 (2000).

    CAS  PubMed  Google Scholar 

  29. Kim, Y. G. et al. Human CD4+CD25+ regulatory T cells inhibit the differentiation of osteoclasts from peripheral blood mononuclear cells. Biochem. Biophys. Res. Commun. 357, 1046–1052 (2007).

    CAS  PubMed  Google Scholar 

  30. Zaiss, M. M. et al. Treg cells suppress osteoclast formation: a new link between the immune system and bone. Arthritis Rheum. 56, 4104–4112 (2007).

    CAS  PubMed  Google Scholar 

  31. Takayanagi, H. Osteoimmunology and the effects of the immune system on bone. Nat. Rev. Rheumatol. 5, 667–676 (2009).

    CAS  PubMed  Google Scholar 

  32. Amara, K. et al. Monoclonal IgG antibodies generated from joint-derived B cells of RA patients have a strong bias toward citrullinated autoantigen recognition. J. Exp. Med. 210, 445–455 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  33. Krishnamurthy, A. et al. Identification of a novel chemokine-dependent molecular mechanism underlying rheumatoid arthritis-associated autoantibody-mediated bone loss. Ann. Rheum. Dis. 75, 721–729 (2016).

    CAS  PubMed  Google Scholar 

  34. Harre, U. et al. Glycosylation of immunoglobulin G determines osteoclast differentiation and bone loss. Nat. Commun. 6, 6651 (2015).

    CAS  PubMed  Google Scholar 

  35. Negishi-Koga, T. et al. Immune complexes regulate bone metabolism through FcRγ signalling. Nat. Commun. 6, 6637 (2015).

    CAS  PubMed  Google Scholar 

  36. Kouskoff, V. et al. Organ-specific disease provoked by systemic autoimmunity. Cell 87, 811–822 (1996).

    CAS  PubMed  Google Scholar 

  37. Ranges, G. E., Sriram, S. & Cooper, S. M. Prevention of type II collagen-induced arthritis by in vivo treatment with anti-L3T4. J. Exp. Med. 162, 1105–1110 (1985).

    CAS  PubMed  Google Scholar 

  38. Kang, Y. M. et al. CD8 T cells are required for the formation of ectopic germinal centers in rheumatoid synovitis. J. Exp. Med. 195, 1325–1336 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  39. MacDonald, K. P., Nishioka, Y., Lipsky, P. E. & Thomas, R. Functional CD40 ligand is expressed by T cells in rheumatoid arthritis. J. Clin. Invest. 100, 2404–2414 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  40. Nakae, S., Nambu, A., Sudo, K. & Iwakura, Y. Suppression of immune induction of collagen-induced arthritis in IL-17-deficient mice. J. Immunol. 171, 6173–6177 (2003).

    CAS  PubMed  Google Scholar 

  41. Lubberts, E. et al. Treatment with a neutralizing anti-murine interleukin-17 antibody after the onset of collagen-induced arthritis reduces joint inflammation, cartilage destruction, and bone erosion. Arthritis Rheum. 50, 650–659 (2004).

    CAS  PubMed  Google Scholar 

  42. Kotake, S. et al. IL-17 in synovial fluids from patients with rheumatoid arthritis is a potent stimulator of osteoclastogenesis. J. Clin. Invest. 103, 1345–1352 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  43. Lubberts, E. et al. IL-17 promotes bone erosion in murine collagen-induced arthritis through loss of the receptor activator of NF-κB ligand/osteoprotegerin balance. J. Immunol. 170, 2655–2662 (2003).

    CAS  PubMed  Google Scholar 

  44. Hirota, K. et al. T cell self-reactivity forms a cytokine milieu for spontaneous development of IL-17+ TH cells that cause autoimmune arthritis. J. Exp. Med. 204, 41–47 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  45. Sato, K. et al. TH17 functions as an osteoclastogenic helper T cell subset that links T cell activation and bone destruction. J. Exp. Med. 203, 2673–2682 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  46. Takayanagi, H. Osteoimmunology: shared mechanisms and crosstalk between the immune and bone systems. Nat. Rev. Immunol. 7, 292–304 (2007).

    CAS  PubMed  Google Scholar 

  47. Komatsu, N. et al. Pathogenic conversion of Foxp3+ T cells into TH17 cells in autoimmune arthritis. Nat. Med. 20, 62–68 (2014).

    CAS  PubMed  Google Scholar 

  48. Belkaid, Y. & Harrison, O. J. Homeostatic immunity and the microbiota. Immunity 46, 562–576 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  49. Kramer, C. D. & Genco, C. A. Microbiota, immune subversion, and chronic inflammation. Front. Immunol. 8, 255 (2017).

    PubMed  PubMed Central  Google Scholar 

  50. Hernandez, C. J., Guss, J. D., Luna, M. & Goldring, S. R. Links between the microbiome and bone. J. Bone Miner. Res. 31, 1638–1646 (2016).

    PubMed  Google Scholar 

  51. Van de Wiele, T., Van Praet, J. T., Marzorati, M., Drennan, M. B. & Elewaut, D. How the microbiota shapes rheumatic diseases. Nat. Rev. Rheumatol. 12, 398–411 (2016).

    CAS  PubMed  Google Scholar 

  52. Kasagi, S. & Chen, W. TGF-β1 on osteoimmunology and the bone component cells. Cell Biosci. 3, 4 (2013).

    PubMed  PubMed Central  Google Scholar 

  53. Nemeth, K. et al. The role of osteoclast-associated receptor in osteoimmunology. J. Immunol. 186, 13–18 (2011).

    CAS  PubMed  Google Scholar 

  54. Proctor, L. M. The National Institutes of Health Human Microbiome Project. Semin. Fetal Neonatal Med. 21, 368–372 (2016).

    PubMed  Google Scholar 

  55. Charbonneau, M. R. et al. A microbial perspective of human developmental biology. Nature 535, 48–55 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  56. Fraiture, M. & Brunner, F. Killing two birds with one stone: trans-kingdom suppression of PAMP/MAMP-induced immunity by T3E from enteropathogenic bacteria. Front. Microbiol. 5, 320 (2014).

    PubMed  PubMed Central  Google Scholar 

  57. Kau, A. L., Ahern, P. P., Griffin, N. W., Goodman, A. L. & Gordon, J. I. Human nutrition, the gut microbiome and the immune system. Nature 474, 327–336 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  58. Scher, J. U. & Abramson, S. B. The microbiome and rheumatoid arthritis. Nat. Rev. Rheumatol. 7, 569–578 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  59. Wu, H. J. et al. Gut-residing segmented filamentous bacteria drive autoimmune arthritis via T helper 17 cells. Immunity 32, 815–827 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  60. Round, J. L. & Mazmanian, S. K. The gut microbiota shapes intestinal immune responses during health and disease. Nat. Rev. Immunol. 9, 313–323 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  61. Al-Asmakh, M. & Zadjali, F. Use of germ-free animal models in microbiota-related research. J. Microbiol. Biotechnol. 25, 1583–1588 (2015).

    PubMed  Google Scholar 

  62. Faith, J. J. et al. Creating and characterizing communities of human gut microbes in gnotobiotic mice. ISME J. 4, 1094–1098 (2010).

    PubMed  Google Scholar 

  63. Mazmanian, S. K., Liu, C. H., Tzianabos, A. O. & Kasper, D. L. An immunomodulatory molecule of symbiotic bacteria directs maturation of the host immune system. Cell 122, 107–118 (2005).

    CAS  PubMed  Google Scholar 

  64. Tanoue, T. & Honda, K. Induction of Treg cells in the mouse colonic mucosa: a central mechanism to maintain host-microbiota homeostasis. Semin. Immunol. 24, 50–57 (2012).

    CAS  PubMed  Google Scholar 

  65. Alunno, A. et al. Altered immunoregulation in rheumatoid arthritis: the role of regulatory T cells and proinflammatory TH17 cells and therapeutic implications. Mediators Inflamm. 2015, 751793 (2015).

    PubMed  PubMed Central  Google Scholar 

  66. Min, Y. W. & Rhee, P. L. The role of microbiota on the gut immunology. Clin. Ther. 37, 968–975 (2015).

    CAS  PubMed  Google Scholar 

  67. Sjögren, K. et al. The gut microbiota regulates bone mass in mice. J. Bone Miner. Res. 27, 1357–1367 (2012).

    PubMed  Google Scholar 

  68. Cho, I. et al. Antibiotics in early life alter the murine colonic microbiome and adiposity. Nature 488, 621–626 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  69. Schwarzer, M. et al. Lactobacillus plantarum strain maintains growth of infant mice during chronic undernutrition. Science 351, 854–857 (2016).

    CAS  PubMed  Google Scholar 

  70. Yan, J. et al. Gut microbiota induce IGF-1 and promote bone formation and growth. Proc. Natl Acad. Sci. USA 113, E7554–E7563 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  71. Iqbal, J. & Zaidi, M. Understanding estrogen action during menopause. Endocrinology 150, 3443–3445 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  72. Li, J. Y. et al. Sex steroid deficiency-associated bone loss is microbiota dependent and prevented by probiotics. J. Clin. Invest. 126, 2049–2063 (2016).

    PubMed  PubMed Central  Google Scholar 

  73. Paster, B. J. et al. Bacterial diversity in human subgingival plaque. J. Bacteriol. 183, 3770–3783 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  74. Costalonga, M. & Herzberg, M. C. The oral microbiome and the immunobiology of periodontal disease and caries. Immunol. Lett. 162, 22–38 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  75. Tompkins, K. A. The osteoimmunology of alveolar bone loss. Connect. Tissue Res. 57, 69–90 (2016).

    CAS  PubMed  Google Scholar 

  76. Taubman, M. A., Valverde, P., Han, X. & Kawai, T. Immune response: the key to bone resorption in periodontal disease. J. Periodontol. 76, 2033–2041 (2005).

    CAS  PubMed  Google Scholar 

  77. Hajishengallis, G. & Lamont, R. J. Beyond the red complex and into more complexity: the polymicrobial synergy and dysbiosis (PSD) model of periodontal disease etiology. Mol. Oral Microbiol. 27, 409–419 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  78. Silva, N. et al. Host response mechanisms in periodontal diseases. J. Appl. Oral Sci. 23, 329–355 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  79. Socransky, S. S., Haffajee, A. D., Cugini, M. A., Smith, C. & Kent, R. L. Jr. Microbial complexes in subgingival plaque. J. Clin. Periodontol. 25, 134–144 (1998).

    CAS  PubMed  Google Scholar 

  80. Irie, K., Novince, C. M. & Darveau, R. P. Impact of the oral commensal flora on alveolar bone homeostasis. J. Dental Res. 93, 801–806 (2014).

    CAS  Google Scholar 

  81. Potempa, J., Mydel, P. & Koziel, J. The case for periodontitis in the pathogenesis of rheumatoid arthritis. Nat. Rev. Rheumatol. 13, 606–620 (2017).

    CAS  PubMed  Google Scholar 

  82. Charles, J. F. & Nakamura, M. C. Bone and the innate immune system. Curr. Osteoporos. Rep. 12, 1–8 (2014).

    PubMed  PubMed Central  Google Scholar 

  83. Elshabrawy, H. A., Essani, A. E., Szekanecz, Z., Fox, D. A. & Shahrara, S. TLRs, future potential therapeutic targets for RA. Autoimmun. Rev. 16, 103–113 (2017).

    CAS  PubMed  Google Scholar 

  84. Bar-Shavit, Z. Taking a toll on the bones: regulation of bone metabolism by innate immune regulators. Autoimmunity 41, 195–203 (2008).

    CAS  PubMed  Google Scholar 

  85. Bonar, S. L. et al. Constitutively activated NLRP3 inflammasome causes inflammation and abnormal skeletal development in mice. PLoS ONE 7, e35979 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  86. Guo, H., Callaway, J. B. & Ting, J. P. Inflammasomes: mechanism of action, role in disease, and therapeutics. Nat. Med. 21, 677–687 (2015).

    PubMed  PubMed Central  Google Scholar 

  87. McCall, S. H. et al. Osteoblasts express NLRP3, a nucleotide-binding domain and leucine-rich repeat region containing receptor implicated in bacterially induced cell death. J. Bone Miner. Res. 23, 30–40 (2008).

    CAS  PubMed  Google Scholar 

  88. Qu, C. et al. NLRP3 mediates osteolysis through inflammation-dependent and -independent mechanisms. FASEB J. 29, 1269–1279 (2015).

    CAS  PubMed  Google Scholar 

  89. Atarashi, K. et al. ATP drives lamina propria TH17 cell differentiation. Nature 455, 808–812 (2008).

    CAS  PubMed  Google Scholar 

  90. Binderman, I., Gadban, N. & Yaffe, A. Extracellular ATP is a key modulator of alveolar bone loss in periodontitis. Arch. Oral Biol. 81, 131–135 (2017).

    CAS  PubMed  Google Scholar 

  91. Turner, C. H. Bone strength: current concepts. Ann. NY Acad. Sci. 1068, 429–446 (2006).

    PubMed  Google Scholar 

  92. Rumney, R. M., Wang, N., Agrawal, A. & Gartland, A. Purinergic signalling in bone. Front. Endocrinol. 3, 116 (2012).

    Google Scholar 

  93. Strazzulla, L. C. & Cronstein, B. N. Regulation of bone and cartilage by adenosine signaling. Purinergic Signal. 12, 583–593 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  94. Burnstock, G. & Boeynaems, J. M. Purinergic signalling and immune cells. Purinergic Signal. 10, 529–564 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  95. Cekic, C. & Linden, J. Purinergic regulation of the immune system. Nat. Rev. Immunol. 16, 177–192 (2016).

    CAS  PubMed  Google Scholar 

  96. Trautmann, A. Extracellular ATP in the immune system: more than just a “danger signal”. Sci. Signal 2, pe6 (2009).

    PubMed  Google Scholar 

  97. Burnstock, G. Purine and pyrimidine receptors. Cell. Mol. Life Sci. 64, 1471–1483 (2007).

    CAS  PubMed  Google Scholar 

  98. Agrawal, A. et al. The effects of P2X7 receptor antagonists on the formation and function of human osteoclasts in vitro. Purinergic Signal. 6, 307–315 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  99. Pellegatti, P., Falzoni, S., Donvito, G., Lemaire, I. & Di Virgilio, F. P2X7 receptor drives osteoclast fusion by increasing the extracellular adenosine concentration. FASEB J. 25, 1264–1274 (2011).

    CAS  PubMed  Google Scholar 

  100. Li, J., Liu, D., Ke, H. Z., Duncan, R. L. & Turner, C. H. The P2X7 nucleotide receptor mediates skeletal mechanotransduction. J. Biol. Chem. 280, 42952–42959 (2005).

    CAS  PubMed  Google Scholar 

  101. Gartland, A. et al. Multinucleated osteoclast formation in vivo and in vitro by P2X7 receptor-deficient mice. Crit. Rev. Eukaryot. Gene Expr 13, 243–253 (2003).

    CAS  PubMed  Google Scholar 

  102. Ke, H. Z. et al. Deletion of the P2X7 nucleotide receptor reveals its regulatory roles in bone formation and resorption. Mol. Endocrinol. 17, 1356–1367 (2003).

    CAS  PubMed  Google Scholar 

  103. Kim, H. et al. The purinergic receptor P2X5 regulates inflammasome activity and hyper-multinucleation of murine osteoclasts. Sci. Rep. 7, 196 (2017).

    PubMed  PubMed Central  Google Scholar 

  104. Giacomelli, R. et al. IL-1β at the crossroad between rheumatoid arthritis and type 2 diabetes: may we kill two birds with one stone? Expert Rev. Clin. Immunol. 12, 849–855 (2016).

    CAS  PubMed  Google Scholar 

  105. Gracie, J. A. et al. A proinflammatory role for IL-18 in rheumatoid arthritis. J. Clin. Invest. 104, 1393–1401 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  106. Perregaux, D. G., McNiff, P., Laliberte, R., Conklyn, M. & Gabel, C. A. ATP acts as an agonist to promote stimulus-induced secretion of IL-1β and IL-18 in human blood. J. Immunol. 165, 4615–4623 (2000).

    CAS  PubMed  Google Scholar 

  107. Caporali, F. et al. Human rheumatoid synoviocytes express functional P2X7 receptors. J. Mol. Med. (Berl.) 86, 937–949 (2008).

    CAS  Google Scholar 

  108. Lopez-Castejon, G. et al. P2X7 receptor-mediated release of cathepsins from macrophages is a cytokine-independent mechanism potentially involved in joint diseases. J. Immunol. 185, 2611–2619 (2010).

    CAS  PubMed  Google Scholar 

  109. Chen, J., Zhao, Y. & Liu, Y. The role of nucleotides and purinergic signaling in apoptotic cell clearance — implications for chronic inflammatory diseases. Front. Immunol. 5, 656 (2014).

    PubMed  PubMed Central  Google Scholar 

  110. Keystone, E. C. et al. Clinical evaluation of the efficacy of the P2X7 purinergic receptor antagonist AZD9056 on the signs and symptoms of rheumatoid arthritis in patients with active disease despite treatment with methotrexate or sulphasalazine. Ann. Rheum. Dis. 71, 1630–1635 (2012).

    CAS  PubMed  Google Scholar 

  111. Stock, T. C. et al. Efficacy and safety of CE-224,535, an antagonist of P2X7 receptor, in treatment of patients with rheumatoid arthritis inadequately controlled by methotrexate. J. Rheumatol. 39, 720–727 (2012).

    CAS  PubMed  Google Scholar 

  112. Mercier, F. E., Ragu, C. & Scadden, D. T. The bone marrow at the crossroads of blood and immunity. Nat. Rev. Immunol. 12, 49–60 (2011).

    PubMed  PubMed Central  Google Scholar 

  113. Lymperi, S. et al. Strontium can increase some osteoblasts without increasing hematopoietic stem cells. Blood 111, 1173–1181 (2008).

    CAS  PubMed  Google Scholar 

  114. Ding, L., Saunders, T. L., Enikolopov, G. & Morrison, S. J. Endothelial and perivascular cells maintain haematopoietic stem cells. Nature 481, 457–462 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  115. Ding, L. & Morrison, S. J. Haematopoietic stem cells and early lymphoid progenitors occupy distinct bone marrow niches. Nature 495, 231–235 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  116. Greenbaum, A. et al. CXCL12 in early mesenchymal progenitors is required for haematopoietic stem-cell maintenance. Nature 495, 227–230 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  117. Nakamura, Y. et al. Isolation and characterization of endosteal niche cell populations that regulate hematopoietic stem cells. Blood 116, 1422–1432 (2010).

    CAS  PubMed  Google Scholar 

  118. Visnjic, D. et al. Hematopoiesis is severely altered in mice with an induced osteoblast deficiency. Blood 103, 3258–3264 (2004).

    CAS  PubMed  Google Scholar 

  119. Zhu, J. et al. Osteoblasts support B-lymphocyte commitment and differentiation from hematopoietic stem cells. Blood 109, 3706–3712 (2007).

    CAS  PubMed  Google Scholar 

  120. Wu, J. Y. et al. Osteoblastic regulation of B lymphopoiesis is mediated by Gsα-dependent signaling pathways. Proc. Natl Acad. Sci. USA 105, 16976–16981 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  121. Yu, V. W. et al. Specific bone cells produce DLL4 to generate thymus-seeding progenitors from bone marrow. J. Exp. Med. 212, 759–774 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  122. Asada, N. et al. Matrix-embedded osteocytes regulate mobilization of hematopoietic stem/progenitor cells. Cell Stem Cell 12, 737–747 (2013).

    CAS  PubMed  Google Scholar 

  123. Fulzele, K. et al. Myelopoiesis is regulated by osteocytes through Gsα-dependent signaling. Blood 121, 930–939 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  124. Mansour, A. et al. Osteoclast activity modulates B-cell development in the bone marrow. Cell Res. 21, 1102–1115 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  125. Kollet, O. et al. Osteoclasts degrade endosteal components and promote mobilization of hematopoietic progenitor cells. Nat. Med. 12, 657–664 (2006).

    CAS  PubMed  Google Scholar 

  126. Miyamoto, K. et al. Osteoclasts are dispensable for hematopoietic stem cell maintenance and mobilization. J. Exp. Med. 208, 2175–2181 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  127. Chen, W. et al. Arthritogenic alphaviral infection perturbs osteoblast function and triggers pathologic bone loss. Proc. Natl Acad. Sci. USA 111, 6040–6045 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  128. Tang, T. T., Zhang, L., Bansal, A., Grynpas, M. & Moriatry, T. J. The Lyme disease pathogen Borrelia burgdorferi infects murine bone and induces trabecular bone loss. Infect. Immun. 85, e00781-16 (2017).

    PubMed  PubMed Central  Google Scholar 

  129. Terashima, A. et al. Sepsis-induced osteoblast ablation causes immunodeficiency. Immunity 44, 1434–1443 (2016).

    CAS  PubMed  Google Scholar 

  130. Day, R. B., Bhattacharya, D., Nagasawa, T. & Link, D. C. Granulocyte colony-stimulating factor reprograms bone marrow stromal cells to actively suppress B lymphopoiesis in mice. Blood 125, 3114–3117 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  131. Kanematsu, M. et al. Prostaglandin E2 induces expression of receptor activator of nuclear factor-κB ligand/osteoprotegrin ligand on pre-B cells: implications for accelerated osteoclastogenesis in estrogen deficiency. J. Bone Miner. Res. 15, 1321–1329 (2000).

    CAS  PubMed  Google Scholar 

  132. Cenci, S. et al. Estrogen deficiency induces bone loss by enhancing T-cell production of TNF-α. J. Clin. Invest. 106, 1229–1237 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  133. Roggia, C. et al. Up-regulation of TNF-producing T cells in the bone marrow: a key mechanism by which estrogen deficiency induces bone loss in vivo. Proc. Natl Acad. Sci. USA 98, 13960–13965 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  134. Lee, S. K. et al. T lymphocyte-deficient mice lose trabecular bone mass with ovariectomy. J. Bone Miner. Res. 21, 1704–1712 (2006).

    CAS  PubMed  Google Scholar 

  135. D'Amelio, P. et al. Estrogen deficiency increases osteoclastogenesis up-regulating T cells activity: a key mechanism in osteoporosis. Bone 43, 92–100 (2008).

    CAS  PubMed  Google Scholar 

  136. Eghbali-Fatourechi, G. et al. Role of RANK ligand in mediating increased bone resorption in early postmenopausal women. J. Clin. Invest. 111, 1221–1230 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  137. Onal, M. et al. Receptor activator of nuclear factor κB ligand (RANKL) protein expression by B lymphocytes contributes to ovariectomy-induced bone loss. J. Biol. Chem. 287, 29851–29860 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  138. Li, Y., Li, A., Yang, X. & Weitzmann, M. N. Ovariectomy-induced bone loss occurs independently of B cells. J. Cell. Biochem. 100, 1370–1375 (2007).

    CAS  PubMed  Google Scholar 

  139. Perlot, T. & Penninger, J. M. Development and function of murine B cells lacking RANK. J. Immunol. 188, 1201–1205 (2012).

    CAS  PubMed  Google Scholar 

  140. Xiong, J. et al. Matrix-embedded cells control osteoclast formation. Nat. Med. 17, 1235–1241 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  141. Nakashima, T. et al. Evidence for osteocyte regulation of bone homeostasis through RANKL expression. Nat. Med. 17, 1231–1234 (2011).

    CAS  PubMed  Google Scholar 

  142. Fujiwara, Y. et al. RANKL (receptor activator of NF-κB ligand) produced by osteocytes is required for the increase in B cells and bone loss caused by estrogen deficiency in mice. J. Biol. Chem. 291, 24838–24850 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  143. Boyce, B. F., Yoneda, T., Lowe, C., Soriano, P. & Mundy, G. R. Requirement of pp60c-Src expression for osteoclasts to form ruffled borders and resorb bone in mice. J. Clin. Invest. 90, 1622–1627 (1992).

    CAS  PubMed  PubMed Central  Google Scholar 

  144. Ishimi, Y. et al. IL-6 is produced by osteoblasts and induces bone resorption. J. Immunol. 145, 3297–3303 (1990).

    CAS  PubMed  Google Scholar 

  145. Danks, L. et al. RANKL expressed on synovial fibroblasts is primarily responsible for bone erosions during joint inflammation. Ann. Rheumat. Diseases 75, 1187–1195 (2016).

    CAS  Google Scholar 

  146. Humphrey, M. B. & Nakamura, M. C. A comprehensive review of immunoreceptor regulation of osteoclasts. Clin. Rev. Allergy Immunol. 51, 48–58 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

The work of the authors was supported in part by NIH grants AR069546, AR067726, AI64909, and AI125284 awarded to Y.C.

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  1. Department of Pathology and Laboratory Medicine, University of Pennsylvania Perelman School of Medicine, 421 Curie Boulevard, Philadelphia, 19104, Pennsylvania, USA

    Matthew C. Walsh, Noriko Takegahara, Hyunsoo Kim & Yongwon Choi

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All authors researched the data for the article, provided substantial contributions to discussions of its content, wrote the article and reviewed and/or edited the manuscript before submission.

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Correspondence to Yongwon Choi.

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Walsh, M., Takegahara, N., Kim, H. et al. Updating osteoimmunology: regulation of bone cells by innate and adaptive immunity. Nat Rev Rheumatol 14, 146–156 (2018). https://doi.org/10.1038/nrrheum.2017.213

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