Osteoimmunology: evolving concepts in bone–immune interactions in health and disease

Abstract

In terrestrial vertebrates, bone tissue constitutes the ‘osteoimmune’ system, which functions as a locomotor organ and a mineral reservoir as well as a primary lymphoid organ where haematopoietic stem cells are maintained. Bone and mineral metabolism is maintained by the balanced action of bone cells such as osteoclasts, osteoblasts and osteocytes, yet subverted by aberrant and/or prolonged immune responses under pathological conditions. However, osteoimmune interactions are not restricted to the unidirectional effect of the immune system on bone metabolism. In recent years, we have witnessed the discovery of effects of bone cells on immune regulation, including the function of osteoprogenitor cells in haematopoietic stem cell regulation and osteoblast-mediated suppression of haematopoietic malignancies. Moreover, the dynamic reciprocal interactions between bone and malignancies in remote organs have attracted attention, extending the horizon of osteoimmunology. Here, we discuss emerging concepts in the osteoimmune dialogue in health and disease.

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Fig. 1: Co-evolution of immune and skeletal systems.
Fig. 2: Osteoclast signalling network.
Fig. 3: Contributions of bone cells to immune regulation.
Fig. 4: Reciprocal interactions of bone and immune cells in systemic diseases.
Fig. 5: Molecular mechanisms of bone destruction in RA.
Fig. 6: Host defence against oral microorganisms through osteoimmune interplay.

References

  1. 1.

    Okamoto, K. et al. Osteoimmunology: the conceptual framework unifying the immune and skeletal systems. Physiol. Rev. 97, 1295–1349 (2017).

    CAS  PubMed  Google Scholar 

  2. 2.

    Horton, J. E., Raisz, L. G., Simmons, H. A., Oppenheim, J. J. & Mergenhagen, S. E. Bone resorbing activity in supernatant fluid from cultured human peripheral blood leukocytes. Science 177, 793–795 (1972).

    CAS  PubMed  Google Scholar 

  3. 3.

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

    CAS  PubMed  Google Scholar 

  4. 4.

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

    CAS  PubMed  Google Scholar 

  5. 5.

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

    CAS  PubMed  Google Scholar 

  6. 6.

    Bouillon, R. & Suda, T. Vitamin D: calcium and bone homeostasis during evolution. Bonekey Rep. 3, 480 (2014).

    PubMed  PubMed Central  Google Scholar 

  7. 7.

    Weiss, M. C. et al. The physiology and habitat of the last universal common ancestor. Nat. Microbiol. 1, 16116 (2016).

    CAS  PubMed  Google Scholar 

  8. 8.

    Costello, M. J. & Chaudhary, C. Marine biodiversity, biogeography, deep-sea gradients, and conservation. Curr. Biol. 27, 2051 (2017).

    CAS  PubMed  Google Scholar 

  9. 9.

    You, X. et al. Mudskipper genomes provide insights into the terrestrial adaptation of amphibious fishes. Nat. Commun. 5, 5594 (2014). This report suggests that the immune system rapidly evolved during the water-to-land transition to provide defence against terrestrial pathogens.

    CAS  PubMed  PubMed Central  Google Scholar 

  10. 10.

    Ishii, A., Kawasaki, M., Matsumoto, M., Tochinai, S. & Seya, T. Phylogenetic and expression analysis of amphibian Xenopus Toll-like receptors. Immunogenetics 59, 281–293 (2007).

    CAS  PubMed  Google Scholar 

  11. 11.

    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 

  12. 12.

    Tsukasaki, M. et al. LOX fails to substitute for RANKL in osteoclastogenesis. J. Bone Miner. Res. 32, 434–439 (2017).

    CAS  PubMed  Google Scholar 

  13. 13.

    Hikosaka, Y. et al. The cytokine RANKL produced by positively selected thymocytes fosters medullary thymic epithelial cells that express autoimmune regulator. Immunity 29, 438–450 (2008).

    CAS  Google Scholar 

  14. 14.

    Mueller, C. G. & Hess, E. Emerging functions of RANKL in lymphoid tissues. Front. Immunol. 3, 261 (2012).

    PubMed  PubMed Central  Google Scholar 

  15. 15.

    Onder, L. et al. Lymphatic endothelial cells control initiation of lymph node organogenesis. Immunity 47, 80–92 (2017).

    CAS  PubMed  Google Scholar 

  16. 16.

    Nagashima, K. et al. Identification of subepithelial mesenchymal cells that induce IgA and diversify gut microbiota. Nat. Immunol. 18, 675–682 (2017).

    CAS  PubMed  Google Scholar 

  17. 17.

    Loser, K. et al. Epidermal RANKL controls regulatory T cell numbers via activation of dendritic cells. Nat. Med. 12, 1372–1379 (2006).

    CAS  PubMed  Google Scholar 

  18. 18.

    Habbeddine, M. et al. Receptor activator of NF-κB orchestrates activation of antiviral memory CD8 T cells in the spleen marginal zone. Cell Rep. 21, 2515–2527 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  19. 19.

    Bando, J. K. et al. The tumor necrosis factor superfamily member RANKL suppresses effector cytokine production in group 3 innate lymphoid cells. Immunity 48, 1208–1219 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  20. 20.

    Fata, J. E. et al. The osteoclast differentiation factor osteoprotegerin-ligand is essential for mammary gland development. Cell 103, 41–50 (2000).

    CAS  PubMed  Google Scholar 

  21. 21.

    Sigl, V. et al. RANKL/RANK control Brca1 mutation-driven mammary tumors. Cell Res. 26, 761–774 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  22. 22.

    Gonzalez-Suarez, E. et al. RANK ligand mediates progestin-induced mammary epithelial proliferation and carcinogenesis. Nature 468, 103–107 (2010).

    CAS  PubMed  Google Scholar 

  23. 23.

    Nolan, E. et al. RANK ligand as a potential target for breast cancer prevention in BRCA1-mutation carriers. Nat. Med. 22, 933–939 (2016).

    CAS  PubMed  Google Scholar 

  24. 24.

    Duheron, V. et al. Receptor activator of NF-kappaB (RANK) stimulates the proliferation of epithelial cells of the epidermo-pilosebaceous unit. Proc. Natl Acad. Sci. USA 108, 5342–5347 (2011).

    CAS  PubMed  Google Scholar 

  25. 25.

    Luo, J. L. et al. Nuclear cytokine-activated IKKalpha controls prostate cancer metastasis by repressing Maspin. Nature 446, 690–694 (2007).

    CAS  PubMed  Google Scholar 

  26. 26.

    Rao, S. et al. RANK rewires energy homeostasis in lung cancer cells and drives primary lung cancer. Genes Dev. 31, 2099–2112 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  27. 27.

    Schramek, D. et al. Osteoclast differentiation factor RANKL controls development of progestin-driven mammary cancer. Nature 468, 98–102 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  28. 28.

    Joshi, P. A. et al. Progesterone induces adult mammary stem cell expansion. Nature 465, 803–807 (2010).

    CAS  PubMed  Google Scholar 

  29. 29.

    Hanada, R. et al. Central control of fever and female body temperature by RANKL/RANK. Nature 462, 505–509 (2009).

    CAS  PubMed  Google Scholar 

  30. 30.

    Kiechl, S. et al. Blockade of receptor activator of nuclear factor-κB (RANKL) signaling improves hepatic insulin resistance and prevents development of diabetes mellitus. Nat. Med. 19, 358–363 (2013).

    CAS  PubMed  Google Scholar 

  31. 31.

    Kondegowda, N. G. et al. Osteoprotegerin and denosumab stimulate human beta cell proliferation through inhibition of the receptor activator of NF-κB ligand pathway. Cell Metab. 22, 77–85 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  32. 32.

    Shoji-Matsunaga, A. et al. Osteocyte regulation of orthodontic force-mediated tooth movement via RANKL expression. Sci. Rep. 7, 8753 (2017).

    PubMed  PubMed Central  Google Scholar 

  33. 33.

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

    CAS  PubMed  Google Scholar 

  34. 34.

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

    CAS  PubMed  PubMed Central  Google Scholar 

  35. 35.

    Fujiwara, Y. et al. RANKL (receptor activator of NFκB 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 

  36. 36.

    Tan, W. et al. Tumour-infiltrating regulatory T cells stimulate mammary cancer metastasis through RANKL-RANK signalling. Nature 470, 548–553 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  37. 37.

    Panizo, S. et al. RANKL increases vascular smooth muscle cell calcification through a RANK-BMP4-dependent pathway. Circ. Res. 104, 1041–1048 (2009).

    CAS  PubMed  Google Scholar 

  38. 38.

    Shimamura, M. et al. OPG/RANKL/RANK axis is a critical inflammatory signaling system in ischemic brain in mice. Proc. Natl Acad. Sci. USA 111, 8191–8196 (2014).

    CAS  PubMed  Google Scholar 

  39. 39.

    Jones, D. H. et al. Regulation of cancer cell migration and bone metastasis by RANKL. Nature 440, 692–696 (2006).

    CAS  PubMed  Google Scholar 

  40. 40.

    Guerrini, M. M. et al. Inhibition of the TNF family cytokine RANKL prevents autoimmune inflammation in the central nervous system. Immunity 43, 1174–1185 (2015).

    CAS  PubMed  Google Scholar 

  41. 41.

    Venkatesh, B. et al. Elephant shark genome provides unique insights into gnathostome evolution. Nature 505, 174–179 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  42. 42.

    Koga, T. et al. Costimulatory signals mediated by the ITAM motif cooperate with RANKL for bone homeostasis. Nature 428, 758–763 (2004).

    CAS  PubMed  Google Scholar 

  43. 43.

    Takayanagi, H. et al. Induction and activation of the transcription factor NFATc1 (NFAT2) integrate RANKL signaling in terminal differentiation of osteoclasts. Dev. Cell 3, 889–901 (2002).

    CAS  PubMed  Google Scholar 

  44. 44.

    Shinohara, M. et al. Tyrosine kinases Btk and Tec regulate osteoclast differentiation by linking RANK and ITAM signals. Cell 132, 794–806 (2008).

    CAS  PubMed  Google Scholar 

  45. 45.

    Asagiri, M. et al. Autoamplification of NFATc1 expression determines its essential role in bone homeostasis. J. Exp. Med. 202, 1261–1269 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  46. 46.

    Negishi-Koga, T. et al. Immune complexes regulate bone metabolism through FcRγ signalling. Nat. Commun. 6, 6637 (2015). This paper shows that immune complexes directly promote osteoclastogenesis.

    CAS  PubMed  Google Scholar 

  47. 47.

    Morrison, S. J. & Scadden, D. T. The bone marrow niche for haematopoietic stem cells. Nature 505, 327–334 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  48. 48.

    Orkin, S. H. & Zon, L. I. Hematopoiesis: an evolving paradigm for stem cell biology. Cell 132, 631–644 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  49. 49.

    Kapp, F. G. et al. Protection from UV light is an evolutionarily conserved feature of the haematopoietic niche. Nature 558, 445–448 (2018). This study suggests that higher levels of ultraviolet light in the terrestrial environment might be an evolutionary pressure that drives HSC homing to the bone marrow.

    CAS  PubMed  PubMed Central  Google Scholar 

  50. 50.

    Adams, G. B. et al. Stem cell engraftment at the endosteal niche is specified by the calcium-sensing receptor. Nature 439, 599–603 (2006).

    CAS  PubMed  Google Scholar 

  51. 51.

    Takubo, K. et al. Regulation of the HIF-1alpha level is essential for hematopoietic stem cells. Cell Stem Cell 7, 391–402 (2010).

    CAS  PubMed  Google Scholar 

  52. 52.

    Spencer, J. A. et al. Direct measurement of local oxygen concentration in the bone marrow of live animals. Nature 508, 269–273 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  53. 53.

    Calvi, L. M. et al. Osteoblastic cells regulate the haematopoietic stem cell niche. Nature 425, 841–846 (2003).

    CAS  PubMed  Google Scholar 

  54. 54.

    Zhang, J. et al. Identification of the haematopoietic stem cell niche and control of the niche size. Nature 425, 836–841 (2003).

    CAS  PubMed  Google Scholar 

  55. 55.

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

    CAS  PubMed  Google Scholar 

  56. 56.

    Greenbaum, A. et al. CXCL12 in early mesenchymal progenitors is required for haematopoietic stem-cell maintenance. Nature 495, 227–230 (2013). This is one of the studies showing the role of osteoprogenitors in HSC maintenance.

    CAS  PubMed  PubMed Central  Google Scholar 

  57. 57.

    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 

  58. 58.

    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 

  59. 59.

    Omatsu, Y. et al. The essential functions of adipo-osteogenic progenitors as the hematopoietic stem and progenitor cell niche. Immunity 33, 387–399 (2010).

    CAS  PubMed  Google Scholar 

  60. 60.

    Xu, C. et al. Stem cell factor is selectively secreted by arterial endothelial cells in bone marrow. Nat. Commun. 9, 2449 (2018).

    PubMed  PubMed Central  Google Scholar 

  61. 61.

    Asada, N. et al. Differential cytokine contributions of perivascular haematopoietic stem cell niches. Nat. Cell Biol. 19, 214–223 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  62. 62.

    Zhou, B. O., Yue, R., Murphy, M. M., Peyer, J. G. & Morrison, S. J. Leptin-receptor-expressing mesenchymal stromal cells represent the main source of bone formed by adult bone marrow. Cell Stem Cell 15, 154–168 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  63. 63.

    Mizoguchi, T. et al. Osterix marks distinct waves of primitive and definitive stromal progenitors during bone marrow development. Dev. Cell 29, 340–349 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  64. 64.

    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 

  65. 65.

    Miyaura, C. et al. Increased B-lymphopoiesis by interleukin 7 induces bone loss in mice with intact ovarian function: similarity to estrogen deficiency. Proc. Natl Acad. Sci. USA 94, 9360–9365 (1997).

    CAS  PubMed  Google Scholar 

  66. 66.

    Lee, S. K. et al. Interleukin-7 influences osteoclast function in vivo but is not a critical factor in ovariectomy-induced bone loss. J. Bone Miner. Res. 21, 695–702 (2006).

    PubMed  Google Scholar 

  67. 67.

    Terashima, A. et al. Sepsis-induced osteoblast ablation causes immunodeficiency. Immunity 44, 1434–1443 (2016). This paper reveals the role of reciprocal interactions between osteoblasts and immune cells during sepsis.

    CAS  PubMed  Google Scholar 

  68. 68.

    Himburg, H. A. et al. Dickkopf-1 promotes hematopoietic regeneration via direct and niche-mediated mechanisms. Nat. Med. 23, 91–99 (2017).

    CAS  PubMed  Google Scholar 

  69. 69.

    Rankin, E. B. et al. The HIF signaling pathway in osteoblasts directly modulates erythropoiesis through the production of EPO. Cell 149, 63–74 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  70. 70.

    Raaijmakers, M. H. et al. Bone progenitor dysfunction induces myelodysplasia and secondary leukaemia. Nature 464, 852–857 (2010). This was the first in vivo evidence for the involvement of osteoblastic cells in the development of haematologic malignancy.

    CAS  PubMed  PubMed Central  Google Scholar 

  71. 71.

    Kode, A. et al. Leukaemogenesis induced by an activating β-catenin mutation in osteoblasts. Nature 506, 240–244 (2014). The authors show that activation of β-catenin in osteoblasts leads to the development of leukaemia.

    CAS  PubMed  PubMed Central  Google Scholar 

  72. 72.

    Kode, A. et al. FoxO1-dependent induction of acute myeloid leukemia by osteoblasts in mice. Leukemia 30, 1–13 (2016).

    CAS  PubMed  Google Scholar 

  73. 73.

    Dong, L. et al. Leukaemogenic effects of Ptpn11 activating mutations in the stem cell microenvironment. Nature 539, 304–308 (2016). This report shows that the activating mutations of SHP2 in osteoprogenitors results in the development of acute myeloid leukaemia.

    PubMed  PubMed Central  Google Scholar 

  74. 74.

    Menendez, P. et al. Bone marrow mesenchymal stem cells from infants with MLL-AF4+ acute leukemia harbor and express the MLL-AF4 fusion gene. J. Exp. Med. 206, 3131–3141 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  75. 75.

    Blau, O. et al. Chromosomal aberrations in bone marrow mesenchymal stroma cells from patients with myelodysplastic syndrome and acute myeloblastic leukemia. Exp. Hematol. 35, 221–229 (2007).

    CAS  PubMed  Google Scholar 

  76. 76.

    Tefferi, A. & Vardiman, J. W. Myelodysplastic syndromes. N. Engl. J. Med. 361, 1872–1885 (2009).

    CAS  PubMed  Google Scholar 

  77. 77.

    Flynn, C. M. & Kaufman, D. S. Donor cell leukemia: insight into cancer stem cells and the stem cell niche. Blood 109, 2688–2692 (2007).

    CAS  PubMed  Google Scholar 

  78. 78.

    Hawkins, E. D. et al. T cell acute leukaemia exhibits dynamic interactions with bone marrow microenvironments. Nature 538, 518–522 (2016).

    PubMed  PubMed Central  Google Scholar 

  79. 79.

    Krevvata, M. et al. Inhibition of leukemia cell engraftment and disease progression in mice by osteoblasts. Blood 124, 2834–2846 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  80. 80.

    Krause, D. S. et al. Differential regulation of myeloid leukemias by the bone marrow microenvironment. Nat. Med. 19, 1513–1517 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  81. 81.

    Shono, Y. et al. Bone marrow graft-versus-host disease: early destruction of hematopoietic niche after MHC-mismatched hematopoietic stem cell transplantation. Blood 115, 5401–5411 (2010).

    CAS  PubMed  Google Scholar 

  82. 82.

    D’Amico, L. et al. Dickkopf-related protein 1 (Dkk1) regulates the accumulation and function of myeloid derived suppressor cells in cancer. J. Exp. Med. 213, 827–840 (2016). This study shows that bone–immune interactions contribute to extraskeletal tumour growth.

    PubMed  PubMed Central  Google Scholar 

  83. 83.

    Engblom, C. et al. Osteoblasts remotely supply lung tumors with cancer-promoting SiglecFhigh neutrophils. Science 358, eaal5081 (2017). The authors show that osteoblasts supply lung tumours with pathogenic neutrophils, which promote tumour growth in the lung.

    PubMed  PubMed Central  Google Scholar 

  84. 84.

    Sreehari, S., Naik, D. R. & Eapen, M. Osteopetrosis: a rare cause of anemia. Hematol. Rep. 3, e1 (2011).

    PubMed  PubMed Central  Google Scholar 

  85. 85.

    Reeves, J. D., August, C. S., Humbert, J. R. & Weston, W. L. Host defense in infantile osteopetrosis. Pediatrics 64, 202–206 (1979).

    CAS  PubMed  Google Scholar 

  86. 86.

    Gerritsen, E. J. et al. Autosomal recessive osteopetrosis: variability of findings at diagnosis and during the natural course. Pediatrics 93, 247–253 (1994).

    CAS  PubMed  Google Scholar 

  87. 87.

    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 

  88. 88.

    Shivtiel, S. et al. CD45 regulates retention, motility, and numbers of hematopoietic progenitors, and affects osteoclast remodeling of metaphyseal trabecules. J. Exp. Med. 205, 2381–2395 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  89. 89.

    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 

  90. 90.

    Rao, M., Supakorndej, T., Schmidt, A. P. & Link, D. C. Osteoclasts are dispensable for hematopoietic progenitor mobilization by granulocyte colony-stimulating factor in mice. Exp. Hematol. 43, 110–114 (2015).

    CAS  PubMed  Google Scholar 

  91. 91.

    Mansour, A. et al. Osteoclasts promote the formation of hematopoietic stem cell niches in the bone marrow. J. Exp. Med. 209, 537–549 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  92. 92.

    Lymperi, S., Ersek, A., Ferraro, F., Dazzi, F. & Horwood, N. J. Inhibition of osteoclast function reduces hematopoietic stem cell numbers in vivo. Blood 117, 1540–1549 (2011).

    CAS  PubMed  Google Scholar 

  93. 93.

    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 

  94. 94.

    Teufel, S. et al. Inhibition of bone remodeling in young mice by bisphosphonate displaces the plasma cell niche into the spleen. J. Immunol. 193, 223–233 (2014).

    CAS  PubMed  Google Scholar 

  95. 95.

    Charles, J. F. et al. Inflammatory arthritis increases mouse osteoclast precursors with myeloid suppressor function. J. Clin. Invest. 122, 4592–4605 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  96. 96.

    Yamazaki, S. et al. Nonmyelinating Schwann cells maintain hematopoietic stem cell hibernation in the bone marrow niche. Cell 147, 1146–1158 (2011).

    CAS  PubMed  Google Scholar 

  97. 97.

    Matsumoto, T. & Abe, M. TGF-β-related mechanisms of bone destruction in multiple myeloma. Bone 48, 129–134 (2011).

    CAS  PubMed  Google Scholar 

  98. 98.

    Sato, M. et al. Osteocytes regulate primary lymphoid organs and fat metabolism. Cell Metab. 18, 749–758 (2013).

    CAS  PubMed  Google Scholar 

  99. 99.

    Cain, C. J. et al. Absence of sclerostin adversely affects B cell survival. J. Bone Miner. Res. 27, 1451–1461 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  100. 100.

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

    CAS  PubMed  PubMed Central  Google Scholar 

  101. 101.

    Firestein, G. S. Evolving concepts of rheumatoid arthritis. Nature 423, 356–361 (2003).

    CAS  PubMed  Google Scholar 

  102. 102.

    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 

  103. 103.

    Okada, Y. et al. Genetics of rheumatoid arthritis contributes to biology and drug discovery. Nature 506, 376–381 (2014).

    CAS  PubMed  Google Scholar 

  104. 104.

    Firestein, G. S. & Zvaifler, N. J. How important are T cells in chronic rheumatoid synovitis? Arthritis Rheum. 33, 768–773 (1990).

    CAS  PubMed  Google Scholar 

  105. 105.

    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 

  106. 106.

    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 

  107. 107.

    Nistala, K. et al. Interleukin-17-producing T cells are enriched in the joints of children with arthritis, but have a reciprocal relationship to regulatory T cell numbers. Arthritis Rheum. 58, 875–887 (2008).

    PubMed  PubMed Central  Google Scholar 

  108. 108.

    Hirota, K. et al. Preferential recruitment of CCR6-expressing Th17 cells to inflamed joints via CCL20 in rheumatoid arthritis and its animal model. J. Exp. Med. 204, 2803–2812 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  109. 109.

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

    CAS  PubMed  Google Scholar 

  110. 110.

    Ciucci, T. et al. Bone marrow Th17 TNFα cells induce osteoclast differentiation, and link bone destruction to IBD. Gut 64, 1072–1081 (2015).

    CAS  PubMed  Google Scholar 

  111. 111.

    Komatsu, N. et al. Pathogenic conversion of Foxp3+ T cells into TH17 cells in autoimmune arthritis. Nat. Med. 20, 62–68 (2014). This study reveals that Foxp3 + T cells convert into T H 17 cells under arthritic conditions.

    CAS  PubMed  Google Scholar 

  112. 112.

    Edwards, J. C. et al. Efficacy of B cell-targeted therapy with rituximab in patients with rheumatoid arthritis. N. Engl. J. Med. 350, 2572–2581 (2004).

    CAS  PubMed  Google Scholar 

  113. 113.

    Harre, U. et al. Induction of osteoclastogenesis and bone loss by human autoantibodies against citrullinated vimentin. J. Clin. Invest. 122, 1791–1802 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  114. 114.

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

    CAS  PubMed  PubMed Central  Google Scholar 

  115. 115.

    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 

  116. 116.

    Pfeifle, R. et al. Regulation of autoantibody activity by the IL-23-TH17 axis determines the onset of autoimmune disease. Nat. Immunol. 18, 104–113 (2017).

    CAS  PubMed  Google Scholar 

  117. 117.

    Rao, D. A. et al. Pathologically expanded peripheral T helper cell subset drives B cells in rheumatoid arthritis. Nature 542, 110–114 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  118. 118.

    Ogura, H. et al. Interleukin-17 promotes autoimmunity by triggering a positive-feedback loop via interleukin-6 induction. Immunity 29, 628–636 (2008).

    CAS  PubMed  Google Scholar 

  119. 119.

    Sawa, S. et al. Autoimmune arthritis associated with mutated interleukin (IL)-6 receptor gp130 is driven by STAT3/IL-7-dependent homeostatic proliferation of CD4+ T cells. J. Exp. Med. 203, 1459–1470 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  120. 120.

    Hirota, K. et al. Autoimmune Th17 cells induced synovial stromal and innate lymphoid cell secretion of the cytokine GM-CSF to initiate and augment autoimmune arthritis. Immunity 48, 1220–1232 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  121. 121.

    Armaka, M., Ospelt, C., Pasparakis, M. & Kollias, G. The p55TNFR-IKK2-Ripk3 axis orchestrates arthritis by regulating death and inflammatory pathways in synovial fibroblasts. Nat. Commun. 9, 618 (2018).

    PubMed  PubMed Central  Google Scholar 

  122. 122.

    Stephenson, W. et al. Single-cell RNA-seq of rheumatoid arthritis synovial tissue using low-cost microfluidic instrumentation. Nat. Commun. 9, 791 (2018).

    PubMed  PubMed Central  Google Scholar 

  123. 123.

    Mizoguchi, F. et al. Functionally distinct disease-associated fibroblast subsets in rheumatoid arthritis. Nat. Commun. 9, 789 (2018).

    PubMed  PubMed Central  Google Scholar 

  124. 124.

    Rauber, S. et al. Resolution of inflammation by interleukin-9-producing type 2 innate lymphoid cells. Nat. Med. 23, 938–944 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  125. 125.

    Omata, Y. et al. Group 2 innate lymphoid cells attenuate inflammatory arthritis and protect from bone destruction in mice. Cell Rep. 24, 169–180 (2018).

    CAS  PubMed  Google Scholar 

  126. 126.

    Chowdhury, K. et al. Synovial IL-9 facilitates neutrophil survival, function and differentiation of Th17 cells in rheumatoid arthritis. Arthritis Res. Ther. 20, 18 (2018).

    PubMed  PubMed Central  Google Scholar 

  127. 127.

    Genovese, M. C. et al. LY2439821, a humanized anti-interleukin-17 monoclonal antibody, in the treatment of patients with rheumatoid arthritis: a phase I randomized, double-blind, placebo-controlled, proof-of-concept study. Arthritis Rheum. 62, 929–939 (2010).

    CAS  PubMed  Google Scholar 

  128. 128.

    Hueber, W. et al. Effects of AIN457, a fully human antibody to interleukin-17A, on psoriasis, rheumatoid arthritis, and uveitis. Sci. Transl Med. 2, 52ra72 (2010).

    PubMed  Google Scholar 

  129. 129.

    Baeten, D. et al. Anti-interleukin-17A monoclonal antibody secukinumab in treatment of ankylosing spondylitis: a randomised, double-blind, placebo-controlled trial. Lancet 382, 1705–1713 (2013).

    CAS  PubMed  Google Scholar 

  130. 130.

    McInnes, I. B. et al. Secukinumab, a human anti-interleukin-17A monoclonal antibody, in patients with psoriatic arthritis (FUTURE 2): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet 386, 1137–1146 (2015).

    CAS  PubMed  Google Scholar 

  131. 131.

    Hajishengallis, G. Periodontitis: from microbial immune subversion to systemic inflammation. Nat. Rev. Immunol. 15, 30–44 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  132. 132.

    Hajishengallis, G. et al. Low-abundance biofilm species orchestrates inflammatory periodontal disease through the commensal microbiota and complement. Cell Host Microbe 10, 497–506 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  133. 133.

    Maekawa, T. et al. Porphyromonas gingivalis manipulates complement and TLR signaling to uncouple bacterial clearance from inflammation and promote dysbiosis. Cell Host Microbe 15, 768–778 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  134. 134.

    Hajishengallis, G., Darveau, R. P. & Curtis, M. A. The keystone-pathogen hypothesis. Nat. Rev. Microbiol. 10, 717–725 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  135. 135.

    Ukai, T., Hara, Y. & Kato, I. Effects of T cell adoptive transfer into nude mice on alveolar bone resorption induced by endotoxin. J. Periodontal Res. 31, 414–422 (1996).

    CAS  PubMed  Google Scholar 

  136. 136.

    Yamaguchi, M. et al. T cells are able to promote lipopolysaccharide-induced bone resorption in mice in the absence of B cells. J. Periodontal Res. 43, 549–555 (2008).

    CAS  PubMed  Google Scholar 

  137. 137.

    Teng, Y. T. et al. Functional human T cell immunity and osteoprotegerin ligand control alveolar bone destruction in periodontal infection. J. Clin. Invest. 106, R59–R67 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  138. 138.

    Baker, P. J., Howe, L., Garneau, J. & Roopenian, D. C. T cell knockout mice have diminished alveolar bone loss after oral infection with Porphyromonas gingivalis. FEMS Immunol. Med. Microbiol. 34, 45–50 (2002).

    CAS  PubMed  Google Scholar 

  139. 139.

    Baker, P. J. et al. CD4(+) T cells and the proinflammatory cytokines gamma interferon and interleukin-6 contribute to alveolar bone loss in mice. Infect. Immun. 67, 2804–2809 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  140. 140.

    Jiao, Y. et al. Induction of bone loss by pathobiont-mediated Nod1 signaling in the oral cavity. Cell Host Microbe 13, 595–601 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  141. 141.

    Abe, T. & Hajishengallis, G. Optimization of the ligature-induced periodontitis model in mice. J. Immunol. Methods 394, 49–54 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  142. 142.

    Tsukasaki, M. et al. Host defense against oral microbiota by bone-damaging T cells. Nat. Commun. 9, 701 (2018). This study provides insights on the origin and biological significance of inflammatory bone destruction.

    PubMed  PubMed Central  Google Scholar 

  143. 143.

    Dutzan, N. et al. On-going mechanical damage from mastication drives homeostatic Th17 cell responses at the oral barrier. Immunity 46, 133–147 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  144. 144.

    Yasuhara, R. et al. Lysine-specific gingipain promotes lipopolysaccharide- and active-vitamin D3-induced osteoclast differentiation by degrading osteoprotegerin. Biochem. J. 419, 159–166 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  145. 145.

    Akiyama, T. et al. Porphyromonas gingivalis-derived lysine gingipain enhances osteoclast differentiation induced by tumor necrosis factor-α and interleukin-1β but suppresses that by interleukin-17A: importance of proteolytic degradation of osteoprotegerin by lysine gingipain. J. Biol. Chem. 289, 15621–15630 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  146. 146.

    Koide, M. et al. Osteoprotegerin-deficient male mice as a model for severe alveolar bone loss: comparison with RANKL-overexpressing transgenic male mice. Endocrinology 154, 773–782 (2013).

    CAS  PubMed  Google Scholar 

  147. 147.

    Dutzan, N. et al. A dysbiotic microbiome triggers TH17 cells to mediate oral mucosal immunopathology in mice and humans. Sci. Transl Med. 10, eaat0797 (2018). This paper shows that patients with genetic defects in T H 17 cell development were protected from periodontitis-induced bone loss.

    PubMed  Google Scholar 

  148. 148.

    Okui, T., Aoki, Y., Ito, H., Honda, T. & Yamazaki, K. The presence of IL-17+/FOXP3+ double-positive cells in periodontitis. J. Dent. Res. 91, 574–579 (2012).

    CAS  PubMed  Google Scholar 

  149. 149.

    Kobayashi, T. et al. Assessment of interleukin-6 receptor inhibition therapy on periodontal condition in patients with rheumatoid arthritis and chronic periodontitis. J. Periodontol. 85, 57–67 (2014).

    CAS  PubMed  Google Scholar 

  150. 150.

    Moutsopoulos, N. M. et al. Interleukin-12 and interleukin-23 blockade in leukocyte adhesion deficiency type 1. N. Engl. J. Med. 376, 1141–1146 (2017). The authors show that inhibition of IL-23/T H 17 cell pathway can ameliorate severe periodontitis in leukocyte adhesion defect type 1 patients.

    CAS  PubMed  PubMed Central  Google Scholar 

  151. 151.

    Ogütcen-Toller, M. et al. Intractable bimaxillary osteomyelitis in osteopetrosis: review of the literature and current therapy. J. Oral Maxillofac. Surg. 68, 167–175 (2010).

    PubMed  Google Scholar 

  152. 152.

    Otto, S. et al. Tooth extraction in patients receiving oral or intravenous bisphosphonate administration: a trigger for BRONJ development? J. Craniomaxillofac. Surg. 43, 847–854 (2015).

    PubMed  Google Scholar 

  153. 153.

    Aguirre, J. I. et al. Oncologic doses of zoledronic acid induce osteonecrosis of the jaw-like lesions in rice rats (Oryzomys palustris) with periodontitis. J. Bone Miner. Res. 27, 2130–2143 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  154. 154.

    Soutome, S. et al. Factors affecting development of medication-related osteonecrosis of the jaw in cancer patients receiving high-dose bisphosphonate or denosumab therapy: is tooth extraction a risk factor? PLOS ONE 13, e0201343 (2018).

    PubMed  PubMed Central  Google Scholar 

  155. 155.

    Reisz, R. R., Scott, D. M., Pynn, B. R. & Modesto, S. P. Osteomyelitis in a Paleozoic reptile: ancient evidence for bacterial infection and its evolutionary significance. Naturwissenschaften 98, 551–555 (2011).

    CAS  PubMed  Google Scholar 

  156. 156.

    Maruyama, K. et al. Nociceptors boost the resolution of fungal osteoinflammation via the TRP channel-CGRP-Jdp2 axis. Cell Rep. 19, 2730–2742 (2017).

    CAS  PubMed  Google Scholar 

  157. 157.

    Lee, M. S. J. et al. Plasmodium products persist in the bone marrow and promote chronic bone loss. Sci. Immunol. 2, eaam8093 (2017).

    PubMed  Google Scholar 

  158. 158.

    Smith-Guzmán, N. E. The skeletal manifestation of malaria: an epidemiological approach using documented skeletal collections. Am. J. Phys. Anthropol. 158, 624–635 (2015).

    PubMed  Google Scholar 

  159. 159.

    Kurihara, N., Reddy, S. V., Menaa, C., Anderson, D. & Roodman, G. D. Osteoclasts expressing the measles virus nucleocapsid gene display a pagetic phenotype. J. Clin. Invest. 105, 607–614 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  160. 160.

    Kurihara, N. et al. Expression of measles virus nucleocapsid protein in osteoclasts induces Paget’s disease-like bone lesions in mice. J. Bone Miner. Res. 21, 446–455 (2006).

    CAS  PubMed  Google Scholar 

  161. 161.

    Raynaud-Messina, B. et al. Bone degradation machinery of osteoclasts: an HIV-1 target that contributes to bone loss. Proc. Natl Acad. Sci. USA 115, E2556–E2565 (2018).

    CAS  PubMed  Google Scholar 

  162. 162.

    Lee, J. W. et al. The HIV co-receptor CCR5 regulates osteoclast function. Nat. Commun. 8, 2226 (2017).

    PubMed  PubMed Central  Google Scholar 

  163. 163.

    Maltby, S. et al. Osteoblasts are rapidly ablated by virus-induced systemic inflammation following lymphocytic choriomeningitis virus or pneumonia virus of mice infection in mice. J. Immunol. 200, 632–642 (2018).

    CAS  PubMed  Google Scholar 

  164. 164.

    Lukens, J. R. et al. Critical role for inflammasome-independent IL-1β production in osteomyelitis. Proc. Natl Acad. Sci. USA 111, 1066–1071 (2014).

    CAS  PubMed  Google Scholar 

  165. 165.

    Lukens, J. R. et al. Dietary modulation of the microbiome affects autoinflammatory disease. Nature 516, 246–249 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  166. 166.

    Chitu, V. et al. PSTPIP2 deficiency in mice causes osteopenia and increased differentiation of multipotent myeloid precursors into osteoclasts. Blood 120, 3126–3135 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  167. 167.

    Bader-Meunier, B., Van Nieuwenhove, E., Breton, S. & Wouters, C. Bone involvement in monogenic autoinflammatory syndromes. Rheumatology 57, 606–618 (2018).

    CAS  PubMed  Google Scholar 

  168. 168.

    Akitsu, A. et al. IL-1 receptor antagonist-deficient mice develop autoimmune arthritis due to intrinsic activation of IL-17-producing CCR2(+)Vγ6(+)γδ T cells. Nat. Commun. 6, 7464 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  169. 169.

    Ueki, Y. et al. Mutations in the gene encoding c-Abl-binding protein SH3BP2 cause cherubism. Nat. Genet. 28, 125–126 (2001).

    CAS  PubMed  Google Scholar 

  170. 170.

    Ueki, Y. et al. Increased myeloid cell responses to M-CSF and RANKL cause bone loss and inflammation in SH3BP2 “cherubism” mice. Cell 128, 71–83 (2007).

    CAS  PubMed  Google Scholar 

  171. 171.

    Yoshitaka, T. et al. Enhanced TLR-MYD88 signaling stimulates autoinflammation in SH3BP2 cherubism mice and defines the etiology of cherubism. Cell Rep. 8, 1752–1766 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  172. 172.

    Hero, M. et al. Anti-tumor necrosis factor treatment in cherubism — clinical, radiological and histological findings in two children. Bone 52, 347–353 (2013).

    CAS  PubMed  Google Scholar 

  173. 173.

    Farr, J. N. et al. Targeting cellular senescence prevents age-related bone loss in mice. Nat. Med. 23, 1072–1079 (2017). This paper shows that removal of senescent cells can prevent age-related bone loss.

    CAS  PubMed  PubMed Central  Google Scholar 

  174. 174.

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

    CAS  PubMed  PubMed Central  Google Scholar 

  175. 175.

    Pacifici, R. Role of T cells in ovariectomy induced bone loss — revisited. J. Bone Miner. Res. 27, 231–239 (2012).

    PubMed  Google Scholar 

  176. 176.

    Li, J. Y. et al. IL-17A is increased in humans with primary hyperparathyroidism and mediates PTH-induced bone loss in mice. Cell Metab. 22, 799–810 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  177. 177.

    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 

  178. 178.

    Uy, H. L. et al. Effects of parathyroid hormone (PTH)-related protein and PTH on osteoclasts and osteoclast precursors in vivo. Endocrinology 136, 3207–3212 (1995).

    CAS  PubMed  Google Scholar 

  179. 179.

    Lopes, E. B. P., Filiberti, A., Husain, S. A. & Humphrey, M. B. Immune contributions to osteoarthritis. Curr. Osteoporos. Rep. 15, 593–600 (2017).

    PubMed  Google Scholar 

  180. 180.

    Sherlock, J. P. et al. IL-23 induces spondyloarthropathy by acting on ROR-γt+ CD3+CD4-CD8- entheseal resident T cells. Nat. Med. 18, 1069–1076 (2012).

    CAS  PubMed  Google Scholar 

  181. 181.

    Brennan, T. A. et al. Mast cell inhibition as a therapeutic approach in fibrodysplasia ossificans progressiva (FOP). Bone 109, 259–266 (2018).

    CAS  PubMed  Google Scholar 

  182. 182.

    Convente, M. R. et al. Depletion of mast cells and macrophages impairs heterotopic ossification in an Acvr1R206H mouse model of fibrodysplasia ossificans progressiva. J. Bone Miner. Res. 33, 269–282 (2018).

    CAS  PubMed  Google Scholar 

  183. 183.

    Torossian, F. et al. Macrophage-derived oncostatin M contributes to human and mouse neurogenic heterotopic ossifications. JCI Insight 2, e96034 (2017).

    PubMed Central  Google Scholar 

  184. 184.

    Sage, A. P., Tintut, Y. & Demer, L. L. Regulatory mechanisms in vascular calcification. Nat. Rev. Cardiol. 7, 528–536 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  185. 185.

    Moore, K. J., Sheedy, F. J. & Fisher, E. A. Macrophages in atherosclerosis: a dynamic balance. Nat. Rev. Immunol. 13, 709–721 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  186. 186.

    Al-Aly, Z. et al. Aortic Msx2-Wnt calcification cascade is regulated by TNF-alpha-dependent signals in diabetic Ldlr−/− mice. Arterioscler. Thromb. Vasc. Biol. 27, 2589–2596 (2007).

    CAS  PubMed  Google Scholar 

  187. 187.

    Yu, M. et al. Regulatory T cells are expanded by Teriparatide treatment in humans and mediate intermittent PTH-induced bone anabolism in mice. EMBO Rep. 19, 156–171 (2018).

    CAS  PubMed  Google Scholar 

  188. 188.

    Terauchi, M. et al. T lymphocytes amplify the anabolic activity of parathyroid hormone through Wnt10b signaling. Cell Metab. 10, 229–240 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  189. 189.

    Li, J. Y. et al. The sclerostin-independent bone anabolic activity of intermittent PTH treatment is mediated by T cell-produced Wnt10b. J. Bone Miner. Res. 29, 43–54 (2014).

    PubMed  PubMed Central  Google Scholar 

  190. 190.

    Tyagi, A. M. et al. The microbial metabolite butyrate stimulates bone formation via T regulatory cell-mediated regulation of WNT10B expression. Immunity 49, 1116–1131 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  191. 191.

    Ono, T. et al. IL-17-producing γδ T cells enhance bone regeneration. Nat. Commun. 7, 10928 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

We thank K. Okamoto, T. Nitta, N. Komatsu and A. Terashima for providing helpful discussions during preparation of this manuscript. This work was supported in part by a grant for the Grants-in-Aid for Specially Promoted Research (15H05703) and the Research Fellowship for Young Scientists (18J00744) from the Japan Society for the Promotion of Science (JSPS).

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Glossary

Osteoclast

Multinucleated cell of haematopoietic origin that resorbs bone via acid decalcification and proteolytic degradation.

Osteoblasts

Specialized mesenchymal cells that create bone by secreting bone matrix proteins and promoting mineralization.

Osteocytes

Bone matrix-embedded cells that originate from osteoblasts, functioning as a commander of bone metabolism by controlling osteoblasts and osteoclasts.

Myeloid-derived suppressor cells

(MDSCs). Immature myeloid cells that have the capacity to suppress T cell responses.

Bone marrow mesenchymal stromal cells

Bone marrow cells of mesenchymal origin that contain heterogeneous populations of cells, including mesenchymal stem cells.

Pathogen-associated molecular patterns

(PAMPs). Microorganism-derived molecular structures that are recognized by pattern recognition receptors expressed on innate immune cells.

Danger-associated molecular patterns

(DAMPs). Cell-derived endogenous molecules that are released upon tissue damage and stimulate pattern recognition receptors expressed on innate immune cells.

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Tsukasaki, M., Takayanagi, H. Osteoimmunology: evolving concepts in bone–immune interactions in health and disease. Nat Rev Immunol 19, 626–642 (2019). https://doi.org/10.1038/s41577-019-0178-8

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