1932

Abstract

Osteoclasts are multinucleated cells with the unique ability to resorb bone matrix. Excessive production or activation of osteoclasts leads to skeletal pathologies that affect a significant portion of the population. Although therapies that effectively target osteoclasts have been developed, they are associated with sometimes severe side effects, and a fuller understanding of osteoclast biology may lead to more specific treatments. Along those lines, a rich body of work has defined essential signaling pathways required for osteoclast formation, function, and survival. Nonetheless, recent studies have cast new light on long-held views regarding the origin of these cells during development and homeostasis, their life span, and the cellular sources of factors that drive their production and activity during homeostasis and disease. In this review, we discuss these new findings in the context of existing work and highlight areas of ongoing and future investigation.

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2023-01-24
2024-05-06
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Literature Cited

  1. 1.
    Perez-Amodio S, Jansen DC, Schoenmaker T, Vogels IM, Reinheckel T et al. 2006. Calvarial osteoclasts express a higher level of tartrate-resistant acid phosphatase than long bone osteoclasts and activation does not depend on cathepsin K or L activity. Calcif. Tissue Int. 79:245–54
    [Google Scholar]
  2. 2.
    Everts V, Korper W, Jansen DC, Steinfort J, Lammerse I et al. 1999. Functional heterogeneity of osteoclasts: Matrix metalloproteinases participate in osteoclastic resorption of calvarial bone but not in resorption of long bone. FASEB J. 13:1219–30
    [Google Scholar]
  3. 3.
    Takito J, Nakamura M. 2020. Heterogeneity and actin cytoskeleton in osteoclast and macrophage multinucleation. Int. J. Mol. Sci. 21:6629
    [Google Scholar]
  4. 4.
    Sarafrazi N, Wambogo EA, Shepherd JA. 2021. Osteoporosis or low bone mass in older adults: United States, 2017–2018. NCHS Data Brief 405:1–8
    [Google Scholar]
  5. 5.
    Tu KN, Lie JD, Wan CKV, Cameron M, Austel AG et al. 2018. Osteoporosis: a review of treatment options. P T 43:92–104
    [Google Scholar]
  6. 6.
    Raterman HG, Bultink IE, Lems WF. 2020. Osteoporosis in patients with rheumatoid arthritis: an update in epidemiology, pathogenesis, and fracture prevention. Expert Opin. Pharmacother. 21:1725–37
    [Google Scholar]
  7. 7.
    Mbalaviele G, Novack DV, Schett G, Teitelbaum SL. 2017. Inflammatory osteolysis: a conspiracy against bone. J. Clin. Investig. 127:2030–39
    [Google Scholar]
  8. 8.
    Coleman RE, Croucher PI, Padhani AR, Clezardin P, Chow E et al. 2020. Bone metastases. Nat. Rev. Dis. Primers 6:83
    [Google Scholar]
  9. 9.
    Penna S, Capo V, Palagano E, Sobacchi C, Villa A. 2019. One disease, many genes: implications for the treatment of osteopetroses. Front. Endocrinol. 10:85
    [Google Scholar]
  10. 10.
    Solh H, Da Cunha AM, Giri N, Padmos A, Spence D et al. 1995. Bone marrow transplantation for infantile malignant osteopetrosis. J. Pediatr. Hematol. Oncol. 17:350–55
    [Google Scholar]
  11. 11.
    Blangy A, Bompard G, Guerit D, Marie P, Maurin J et al. 2020. The osteoclast cytoskeleton—current understanding and therapeutic perspectives for osteoporosis. J. Cell Sci. 133:jcs244798
    [Google Scholar]
  12. 12.
    Teitelbaum SL. 2011. The osteoclast and its unique cytoskeleton. Ann. N. Y. Acad. Sci. 1240:14–17
    [Google Scholar]
  13. 13.
    Rogers MJ. 2003. New insights into the molecular mechanisms of action of bisphosphonates. Curr. Pharm. Des. 9:2643–58
    [Google Scholar]
  14. 14.
    Ng PY, Ribet ABP, Pavlos NJ. 2019. Membrane trafficking in osteoclasts and implications for osteoporosis. Biochem. Soc. Trans. 47:639–50
    [Google Scholar]
  15. 15.
    Minoshima M, Kikuta J, Omori Y, Seno S, Suehara R et al. 2019. In vivo multicolor imaging with fluorescent probes revealed the dynamics and function of osteoclast proton pumps. ACS Cent. Sci. 5:1059–66
    [Google Scholar]
  16. 16.
    Ribet ABP, Ng PY, Pavlos NJ. 2021. Membrane transport proteins in osteoclasts: the ins and outs. Front. Cell Dev. Biol. 9:644986
    [Google Scholar]
  17. 17.
    Qin A, Cheng TS, Pavlos NJ, Lin Z, Dai KR, Zheng MH. 2012. V-ATPases in osteoclasts: structure, function and potential inhibitors of bone resorption. Int. J. Biochem. Cell Biol. 44:1422–35
    [Google Scholar]
  18. 18.
    Meadows NA, Sharma SM, Faulkner GJ, Ostrowski MC, Hume DA, Cassady AI. 2007. The expression of Clcn7 and Ostm1 in osteoclasts is coregulated by microphthalmia transcription factor. J. Biol. Chem. 282:1891–904
    [Google Scholar]
  19. 19.
    George A, Zand DJ, Hufnagel RB, Sharma R, Sergeev YV et al. 2016. Biallelic mutations in MITF cause coloboma, osteopetrosis, microphthalmia, macrocephaly, albinism, and deafness. Am. J. Hum. Genet. 99:1388–94
    [Google Scholar]
  20. 20.
    Clarke LA, Hollak CE. 2015. The clinical spectrum and pathophysiology of skeletal complications in lysosomal storage disorders. Best Pract. Res. Clin. Endocrinol. Metab. 29:219–35
    [Google Scholar]
  21. 21.
    Cremasco V, Decker CE, Stumpo D, Blackshear PJ, Nakayama KI et al. 2012. Protein kinase C–delta deficiency perturbs bone homeostasis by selective uncoupling of cathepsin K secretion and ruffled border formation in osteoclasts. J. Bone Miner. Res. 27:2452–63
    [Google Scholar]
  22. 22.
    Drake MT, Clarke BL, Oursler MJ, Khosla S. 2017. Cathepsin K inhibitors for osteoporosis: biology, potential clinical utility, and lessons learned. Endocr. Rev. 38:325–50
    [Google Scholar]
  23. 23.
    Hardy E, Fernandez-Patron C. 2020. Destroy to rebuild: the connection between bone tissue remodeling and matrix metalloproteinases. Front. Physiol. 11:47
    [Google Scholar]
  24. 24.
    Kikuta J, Wada Y, Kowada T, Wang Z, Sun-Wada GH et al. 2013. Dynamic visualization of RANKL and Th17-mediated osteoclast function. J. Clin Investig. 123:866–73
    [Google Scholar]
  25. 25.
    Delaisse JM, Soe K, Andersen TL, Rojek AM, Marcussen N. 2021. The mechanism switching the osteoclast from short to long duration bone resorption. Front. Cell Dev. Biol. 9:644503
    [Google Scholar]
  26. 26.
    Soe K, Delaisse JM. 2017. Time-lapse reveals that osteoclasts can move across the bone surface while resorbing. J. Cell Sci. 130:2026–35
    [Google Scholar]
  27. 27.
    Batoon L, Millard SM, Raggatt LJ, Wu AC, Kaur S et al. 2021. Osteal macrophages support osteoclast-mediated resorption and contribute to bone pathology in a postmenopausal osteoporosis mouse model. J. Bone Miner. Res. 36:2214–28
    [Google Scholar]
  28. 28.
    McDonald MM, Khoo WH, Ng PY, Xiao Y, Zamerli J et al. 2021. Osteoclasts recycle via osteomorphs during RANKL-stimulated bone resorption. Cell 184:1330–47.e13
    [Google Scholar]
  29. 29.
    Park-Min KH. 2019. Metabolic reprogramming in osteoclasts. Semin. Immunopathol. 41:565–72
    [Google Scholar]
  30. 30.
    Indo Y, Takeshita S, Ishii KA, Hoshii T, Aburatani H et al. 2013. Metabolic regulation of osteoclast differentiation and function. J. Bone Miner. Res. 28:2392–99
    [Google Scholar]
  31. 31.
    Lemma S, Sboarina M, Porporato PE, Zini N, Sonveaux P et al. 2016. Energy metabolism in osteoclast formation and activity. Int. J. Biochem. Cell Biol. 79:168–80
    [Google Scholar]
  32. 32.
    Zhang Y, Rohatgi N, Veis DJ, Schilling J, Teitelbaum SL, Zou W. 2018. PGC1β organizes the osteoclast cytoskeleton by mitochondrial biogenesis and activation. J. Bone Miner. Res. 33:1114–25
    [Google Scholar]
  33. 33.
    Nakano S, Inoue K, Xu C, Deng Z, Syrovatkina V et al. 2019. G-protein Gα13 functions as a cytoskeletal and mitochondrial regulator to restrain osteoclast function. Sci. Rep. 9:4236
    [Google Scholar]
  34. 34.
    Bae S, Lee MJ, Mun SH, Giannopoulou EG, Yong-Gonzalez V et al. 2017. MYC-dependent oxidative metabolism regulates osteoclastogenesis via nuclear receptor ERRα. J Clin. Investig. 127:2555–68
    [Google Scholar]
  35. 35.
    Ling W, Krager K, Richardson KK, Warren AD, Ponte F et al. 2021. Mitochondrial Sirt3 contributes to the bone loss caused by aging or estrogen deficiency. JCI Insight 6:e146728
    [Google Scholar]
  36. 36.
    Wiktor-Jedrzejczak W, Bartocci A, Ferrante AW Jr., Ahmed-Ansari A, Sell KW et al. 1990. Total absence of colony-stimulating factor 1 in the macrophage-deficient osteopetrotic (op/op) mouse. PNAS 87:4828–32
    [Google Scholar]
  37. 37.
    Yoshida H, Hayashi S, Kunisada T, Ogawa M, Nishikawa S et al. 1990. The murine mutation osteopetrosis is in the coding region of the macrophage colony stimulating factor gene. Nature 345:442–44
    [Google Scholar]
  38. 38.
    Yao GQ, Wu JJ, Troiano N, Zhu ML, Xiao XY, Insogna K. 2012. Selective deletion of the membrane-bound colony stimulating factor 1 isoform leads to high bone mass but does not protect against estrogen-deficiency bone loss. J. Bone Miner. Metab. 30:408–18
    [Google Scholar]
  39. 39.
    Yao GQ, Troiano N, Simpson CA, Insogna KL. 2017. Selective deletion of the soluble Colony-Stimulating Factor 1 isoform in vivo prevents estrogen-deficiency bone loss in mice. Bone Res. 5:17022
    [Google Scholar]
  40. 40.
    Harris SE, MacDougall M, Horn D, Woodruff K, Zimmer SN et al. 2012. Meox2Cre-mediated disruption of CSF-1 leads to osteopetrosis and osteocyte defects. Bone 50:42–53
    [Google Scholar]
  41. 41.
    Yao GQ, Wu JJ, Ovadia S, Troiano N, Sun BH, Insogna K. 2009. Targeted overexpression of the two colony-stimulating factor-1 isoforms in osteoblasts differentially affects bone loss in ovariectomized mice. Am. J. Physiol. Endocrinol. Metab. 296:E714–20
    [Google Scholar]
  42. 42.
    Baccin C, Al-Sabah J, Velten L, Helbling PM, Grunschlager F et al. 2020. Combined single-cell and spatial transcriptomics reveal the molecular, cellular and spatial bone marrow niche organization. Nat. Cell Biol. 22:38–48
    [Google Scholar]
  43. 43.
    Mun SH, Park PSU, Park-Min KH. 2020. The M-CSF receptor in osteoclasts and beyond. Exp. Mol. Med. 52:1239–54
    [Google Scholar]
  44. 44.
    McDonald MM, Kim AS, Mulholland BS, Rauner M. 2021. New insights into osteoclast biology. JBMR Plus 5:e10539
    [Google Scholar]
  45. 45.
    Jacome-Galarza CE, Percin GI, Muller JT, Mass E, Lazarov T et al. 2019. Developmental origin, functional maintenance and genetic rescue of osteoclasts. Nature 568:541–45
    [Google Scholar]
  46. 46.
    Yahara Y, Barrientos T, Tang YJ, Puviindran V, Nadesan P et al. 2020. Erythromyeloid progenitors give rise to a population of osteoclasts that contribute to bone homeostasis and repair. Nat. Cell Biol. 22:49–59
    [Google Scholar]
  47. 47.
    Sun Y, Li J, Xie X, Gu F, Sui Z et al. 2021. Macrophage-osteoclast associations: origin, polarization, and subgroups. Front. Immunol. 12:778078
    [Google Scholar]
  48. 48.
    Tsukasaki M, Huynh NC, Okamoto K, Muro R, Terashima A et al. 2020. Stepwise cell fate decision pathways during osteoclastogenesis at single-cell resolution. Nat. Metab. 2:1382–90
    [Google Scholar]
  49. 49.
    Tsukasaki M, Takayanagi H. 2019. Osteoimmunology: evolving concepts in bone-immune interactions in health and disease. Nat. Rev. Immunol. 19:626–42
    [Google Scholar]
  50. 50.
    Jimi E, Takakura N, Hiura F, Nakamura I, Hirata-Tsuchiya S. 2019. The role of NF-κB in physiological bone development and inflammatory bone diseases: Is NF-κB inhibition “killing two birds with one stone”?. Cells 8:1636
    [Google Scholar]
  51. 51.
    Kang JY, Kang N, Yang YM, Hong JH, Shin DM. 2020. The role of Ca2+-NFATc1 signaling and its modulation on osteoclastogenesis. Int. J. Mol. Sci. 21:3646
    [Google Scholar]
  52. 52.
    Li S, Miller CH, Giannopoulou E, Hu X, Ivashkiv LB, Zhao B. 2014. RBP-J imposes a requirement for ITAM-mediated costimulation of osteoclastogenesis. J. Clin. Investig. 124:5057–73
    [Google Scholar]
  53. 53.
    Swarnkar G, Shim K, Nasir AM, Seehra K, Chen HP et al. 2016. Myeloid deletion of Nemo causes osteopetrosis in mice owing to upregulation of transcriptional repressors. Sci. Rep. 6:29896
    [Google Scholar]
  54. 54.
    Vaira S, Alhawagri M, Anwisye I, Kitaura H, Faccio R, Novack DV. 2008. RelA/p65 promotes osteoclast differentiation by blocking a RANKL-induced apoptotic JNK pathway in mice. J. Clin. Investig. 118:2088–97
    [Google Scholar]
  55. 55.
    Otero JE, Dai S, Foglia D, Alhawagri M, Vacher J et al. 2008. Defective osteoclastogenesis by IKKβ-null precursors is a result of receptor activator of NF-κB ligand (RANKL)-induced JNK-dependent apoptosis and impaired differentiation. J. Biol. Chem. 283:24546–53
    [Google Scholar]
  56. 56.
    Kurotaki D, Yoshida H, Tamura T. 2020. Epigenetic and transcriptional regulation of osteoclast differentiation. Bone 138:115471
    [Google Scholar]
  57. 57.
    Pal S, Tyler JK. 2016. Epigenetics and aging. Sci. Adv. 2:e1600584
    [Google Scholar]
  58. 58.
    Nishikawa K, Iwamoto Y, Kobayashi Y, Katsuoka F, Kawaguchi S et al. 2015. DNA methyltransferase 3a regulates osteoclast differentiation by coupling to an S-adenosylmethionine-producing metabolic pathway. Nat. Med. 21:281–87
    [Google Scholar]
  59. 59.
    Yasui T, Hirose J, Tsutsumi S, Nakamura K, Aburatani H, Tanaka S. 2011. Epigenetic regulation of osteoclast differentiation: possible involvement of Jmjd3 in the histone demethylation of Nfatc1. J. Bone Miner. Res. 26:2665–71
    [Google Scholar]
  60. 60.
    Fang C, Qiao Y, Mun SH, Lee MJ, Murata K et al. 2016. Cutting edge: EZH2 promotes osteoclastogenesis by epigenetic silencing of the negative regulator IRF8. J. Immunol. 196:4452–56
    [Google Scholar]
  61. 61.
    Adamik J, Pulugulla SH, Zhang P, Sun Q, Lontos K et al. 2020. EZH2 supports osteoclast differentiation and bone resorption via epigenetic and cytoplasmic targets. J. Bone Miner. Res. 35:181–95
    [Google Scholar]
  62. 62.
    Carey HA, Hildreth BE 3rd, Geisler JA, Nickel MC, Cabrera J et al. 2018. Enhancer variants reveal a conserved transcription factor network governed by PU.1 during osteoclast differentiation. Bone Res. 6:8
    [Google Scholar]
  63. 63.
    Izawa N, Kurotaki D, Nomura S, Fujita T, Omata Y et al. 2019. Cooperation of PU.1 with IRF8 and NFATc1 defines chromatin landscapes during RANKL-induced osteoclastogenesis. J. Bone Miner. Res. 34:1143–54
    [Google Scholar]
  64. 64.
    Ibanez L, Abou-Ezzi G, Ciucci T, Amiot V, Belaid N et al. 2016. Inflammatory osteoclasts prime TNFα-producing CD4+ T cells and express CX3CR1. J. Bone Miner. Res. 31:1899–908
    [Google Scholar]
  65. 65.
    Toor SM, Wani S, Albagha OME. 2021. Comprehensive transcriptomic profiling of murine osteoclast differentiation reveals novel differentially expressed genes and LncRNAs. Front. Genet. 12:781272
    [Google Scholar]
  66. 66.
    Li P, Schwarz EM, O'Keefe RJ, Ma L, Boyce BF, Xing L. 2004. RANK signaling is not required for TNFα-mediated increase in CD11bhi osteoclast precursors but is essential for mature osteoclast formation in TNFα-mediated inflammatory arthritis. J. Bone Miner. Res. 19:207–13
    [Google Scholar]
  67. 67.
    Novack DV, Yin L, Hagen-Stapleton A, Schreiber RD, Goeddel DV et al. 2003. The IκB function of NF-κB2 p100 controls stimulated osteoclastogenesis. J. Exp. Med. 198:771–81
    [Google Scholar]
  68. 68.
    Yao Z, Xing L, Boyce BF. 2009. NF-κB p100 limits TNF-induced bone resorption in mice by a TRAF3-dependent mechanism. J. Clin. Investig. 119:3024–34
    [Google Scholar]
  69. 69.
    Zhao B, Grimes SN, Li S, Hu X, Ivashkiv LB. 2012. TNF-induced osteoclastogenesis and inflammatory bone resorption are inhibited by transcription factor RBP-J. J. Exp. Med. 209:319–34
    [Google Scholar]
  70. 70.
    Kim N, Kadono Y, Takami M, Lee J, Lee SH et al. 2005. Osteoclast differentiation independent of the TRANCE-RANK-TRAF6 axis. J. Exp. Med. 202:589–95
    [Google Scholar]
  71. 71.
    O'Brien W, Fissel BM, Maeda Y, Yan J, Ge X et al. 2016. RANK-independent osteoclast formation and bone erosion in inflammatory arthritis. Arthritis Rheumatol. 68:2889–900
    [Google Scholar]
  72. 72.
    Murata K, Uozumi R, Hashimoto M, Ebina K, Akashi K et al. 2022. The real-world effectiveness of anti-RANKL antibody denosumab on the clinical fracture prevention in patients with rheumatoid arthritis: the ANSWER cohort study. Mod. Rheumatol. 32:834–38
    [Google Scholar]
  73. 73.
    Iwamoto N, Sato S, Sumiyoshi R, Chiba K, Miyamoto N et al. 2019. Comparative study of the inhibitory effect on bone erosion progression with denosumab treatment and conventional treatment in rheumatoid arthritis patients: study protocol for an open-label randomized controlled trial by HR-pQCT. Trials 20:494
    [Google Scholar]
  74. 74.
    Kodama J, Kaito T. 2020. Osteoclast multinucleation: review of current literature. Int. J. Mol. Sci. 21:5685
    [Google Scholar]
  75. 75.
    Yagi M, Miyamoto T, Sawatani Y, Iwamoto K, Hosogane N et al. 2005. DC-STAMP is essential for cell-cell fusion in osteoclasts and foreign body giant cells. J. Exp. Med. 202:345–51
    [Google Scholar]
  76. 76.
    Miyamoto H, Suzuki T, Miyauchi Y, Iwasaki R, Kobayashi T et al. 2012. Osteoclast stimulatory transmembrane protein and dendritic cell-specific transmembrane protein cooperatively modulate cell-cell fusion to form osteoclasts and foreign body giant cells. J. Bone Miner. Res. 27:1289–97
    [Google Scholar]
  77. 77.
    Chiu YH, Schwarz E, Li D, Xu Y, Sheu TR et al. 2017. Dendritic cell-specific transmembrane protein (DC-STAMP) regulates osteoclast differentiation via the Ca2+/NFATc1 axis. J. Cell. Physiol. 232:2538–49
    [Google Scholar]
  78. 78.
    Ueki Y, Lin CY, Senoo M, Ebihara T, Agata N et al. 2007. Increased myeloid cell responses to M-CSF and RANKL cause bone loss and inflammation in SH3BP2 “cherubism” mice. Cell 128:71–83
    [Google Scholar]
  79. 79.
    Rabjohns EM, Hurst K, Ghosh A, Cuellar MC, Rampersad RR, Tarrant TK. 2021. Paget's disease of bone: osteoimmunology and osteoclast pathology. Curr. Allergy Asthma Rep. 21:23
    [Google Scholar]
  80. 80.
    Jansen ID, Vermeer JA, Bloemen V, Stap J, Everts V. 2012. Osteoclast fusion and fission. Calcif. Tissue Int. 90:515–22
    [Google Scholar]
  81. 81.
    An E, Narayanan M, Manes NP, Nita-Lazar A. 2014. Characterization of functional reprogramming during osteoclast development using quantitative proteomics and mRNA profiling. Mol. Cell. Proteomics 13:2687–704
    [Google Scholar]
  82. 82.
    Zeng R, Faccio R, Novack DV. 2015. Alternative NF-κB regulates RANKL-induced osteoclast differentiation and mitochondrial biogenesis via independent mechanisms. J. Bone Miner. Res. 30:2287–99
    [Google Scholar]
  83. 83.
    Jin Z, Wei W, Yang M, Du Y, Wan Y. 2014. Mitochondrial complex I activity suppresses inflammation and enhances bone resorption by shifting macrophage-osteoclast polarization. Cell Metab. 20:483–98
    [Google Scholar]
  84. 84.
    Wang L, Fang B, Fujiwara T, Krager K, Gorantla A et al. 2018. Deletion of ferroportin in murine myeloid cells increases iron accumulation and stimulates osteoclastogenesis in vitro and in vivo. J. Biol. Chem. 293:9248–64
    [Google Scholar]
  85. 85.
    Ishii KA, Fumoto T, Iwai K, Takeshita S, Ito M et al. 2009. Coordination of PGC-1β and iron uptake in mitochondrial biogenesis and osteoclast activation. Nat. Med. 15:259–66
    [Google Scholar]
  86. 86.
    Izawa T, Rohatgi N, Fukunaga T, Wang QT, Silva MJ et al. 2015. ASXL2 regulates glucose, lipid, and skeletal homeostasis. Cell Rep. 11:1625–37
    [Google Scholar]
  87. 87.
    Ballard A, Zeng R, Zarei A, Shao C, Cox L et al. 2020. The tethering function of mitofusin2 controls osteoclast differentiation by modulating the Ca2+-NFATc1 axis. J. Biol. Chem. 295:6629–40
    [Google Scholar]
  88. 88.
    Callaway DA, Jiang JX. 2015. Reactive oxygen species and oxidative stress in osteoclastogenesis, skeletal aging and bone diseases. J. Bone Miner. Metab. 33:359–70
    [Google Scholar]
  89. 89.
    Jaworski ZFG, Duck B, Sekaly G. 1981. Kinetics of osteoclasts and their nuclei in evolving secondary Haversian systems. J. Anat. 133:397–405
    [Google Scholar]
  90. 90.
    Akiyama T, Miyazaki T, Bouillet P, Nakamura K, Strasser A, Tanaka S. 2005. In vitro and in vivo assays for osteoclast apoptosis. Biol. Proced. Online 7:48–59
    [Google Scholar]
  91. 91.
    Soysa NS, Alles N. 2019. Positive and negative regulators of osteoclast apoptosis. Bone Rep. 11:100225
    [Google Scholar]
  92. 92.
    Kong YY, Feige U, Sarosi I, Bolon B, Tafuri A et al. 1999. Activated T cells regulate bone loss and joint destruction in adjuvant arthritis through osteoprotegerin ligand. Nature 402:304–9
    [Google Scholar]
  93. 93.
    Kong YY, Yoshida H, Sarosi I, Tan HL, Timms E et al. 1999. OPGL is a key regulator of osteoclastogenesis, lymphocyte development and lymph-node organogenesis. Nature 397:315–23
    [Google Scholar]
  94. 94.
    Bucay N, Sarosi I, Dunstan CR, Morony S, Tarpley J et al. 1998. osteoprotegerin-deficient mice develop early onset osteoporosis and arterial calcification. Genes Dev. 12:1260–68
    [Google Scholar]
  95. 95.
    Udagawa N, Takahashi N, Jimi E, Matsuzaki K, Tsurukai T et al. 1999. Osteoblasts/stromal cells stimulate osteoclast activation through expression of osteoclast differentiation factor/RANKL but not macrophage colony-stimulating factor. Bone 25:517–23
    [Google Scholar]
  96. 96.
    Khosla S, Hofbauer LC. 2017. Osteoporosis treatment: recent developments and ongoing challenges. Lancet Diabetes Endocrinol. 5:898–907
    [Google Scholar]
  97. 97.
    O'Brien CA. 2010. Control of RANKL gene expression. Bone 46:911–19
    [Google Scholar]
  98. 98.
    Nakashima T, Hayashi M, Fukunaga T, Kurata K, Oh-Hora M et al. 2011. Evidence for osteocyte regulation of bone homeostasis through RANKL expression. Nat. Med. 17:1231–34
    [Google Scholar]
  99. 99.
    Xiong J, Onal M, Jilka RL, Weinstein RS, Manolagas SC, O'Brien CA. 2011. Matrix-embedded cells control osteoclast formation. Nat. Med. 17:1235–41
    [Google Scholar]
  100. 100.
    Lu Y, Xie Y, Zhang S, Dusevich V, Bonewald LF, Feng JQ. 2007. DMP1-targeted Cre expression in odontoblasts and osteocytes. J. Dent. Res. 86:320–25
    [Google Scholar]
  101. 101.
    Xiong J, Piemontese M, Onal M, Campbell J, Goellner JJ et al. 2015. Osteocytes, not osteoblasts or lining cells, are the main source of the RANKL required for osteoclast formation in remodeling bone. PLOS ONE 10:e0138189
    [Google Scholar]
  102. 102.
    Onal M, Xiong J, Chen X, Thostenson JD, Almeida M et al. 2012. Receptor activator of nuclear factor κB ligand (RANKL) protein expression by B lymphocytes contributes to ovariectomy-induced bone loss. J. Biol. Chem. 287:29851–60
    [Google Scholar]
  103. 103.
    Almeida M, Han L, Martin-Millan M, Plotkin LI, Stewart SA et al. 2007. Skeletal involution by age-associated oxidative stress and its acceleration by loss of sex steroids. J. Biol. Chem. 282:27285–97
    [Google Scholar]
  104. 104.
    Piemontese M, Almeida M, Robling AG, Kim HN, Xiong J et al. 2017. Old age causes de novo intracortical bone remodeling and porosity in mice. JCI Insight 2:e93771
    [Google Scholar]
  105. 105.
    Kim HN, Xiong J, MacLeod RS, Iyer S, Fujiwara Y et al. 2020. Osteocyte RANKL is required for cortical bone loss with age and is induced by senescence. JCI Insight 5:e138815
    [Google Scholar]
  106. 106.
    Farr JN, Xu M, Weivoda MM, Monroe DG, Fraser DG et al. 2017. Targeting cellular senescence prevents age-related bone loss in mice. Nat. Med. 23:1072–79
    [Google Scholar]
  107. 107.
    Hozumi A, Osaki M, Goto H, Sakamoto K, Inokuchi S, Shindo H. 2009. Bone marrow adipocytes support dexamethasone-induced osteoclast differentiation. Biochem. Biophys. Res. Commun. 382:780–84
    [Google Scholar]
  108. 108.
    Goto H, Osaki M, Fukushima T, Sakamoto K, Hozumi A et al. 2011. Human bone marrow adipocytes support dexamethasone-induced osteoclast differentiation and function through RANKL expression. Biomed. Res. 32:37–44
    [Google Scholar]
  109. 109.
    Takeshita S, Fumoto T, Naoe Y, Ikeda K. 2014. Age-related marrow adipogenesis is linked to increased expression of RANKL. J. Biol. Chem. 289:16699–710
    [Google Scholar]
  110. 110.
    Matsushita Y, Nagata M, Kozloff KM, Welch JD, Mizuhashi K et al. 2020. A Wnt-mediated transformation of the bone marrow stromal cell identity orchestrates skeletal regeneration. Nat. Commun. 11:332
    [Google Scholar]
  111. 111.
    Yu W, Zhong L, Yao L, Wei Y, Gui T et al. 2021. Bone marrow adipogenic lineage precursors promote osteoclastogenesis in bone remodeling and pathologic bone loss. J. Clin. Investig. 131:e140214
    [Google Scholar]
  112. 112.
    Hu Y, Li X, Zhi X, Cong W, Huang B et al. 2021. RANKL from bone marrow adipose lineage cells promotes osteoclast formation and bone loss. EMBO Rep. 22:e52481
    [Google Scholar]
  113. 113.
    Xiong J, Piemontese M, Thostenson JD, Weinstein RS, Manolagas SC, O'Brien CA. 2014. Osteocyte-derived RANKL is a critical mediator of the increased bone resorption caused by dietary calcium deficiency. Bone 66:146–54
    [Google Scholar]
  114. 114.
    Fujiwara Y, Piemontese M, Liu Y, Thostenson JD, Xiong J, O'Brien CA. 2016. 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. 291:24838–50
    [Google Scholar]
  115. 115.
    Zhang J, Link DC. 2016. Targeting of mesenchymal stromal cells by Cre-recombinase transgenes commonly used to target osteoblast lineage cells. J. Bone Miner. Res. 31:2001–7
    [Google Scholar]
  116. 116.
    Lacey DL, Tan HL, Lu J, Kaufman S, Van G et al. 2000. Osteoprotegerin ligand modulates murine osteoclast survival in vitro and in vivo. Am. J. Pathol. 157:435–48
    [Google Scholar]
  117. 117.
    Gerber HP, Vu TH, Ryan AM, Kowalski J, Werb Z, Ferrara N. 1999. VEGF couples hypertrophic cartilage remodeling, ossification and angiogenesis during endochondral bone formation. Nat. Med. 5:623–28
    [Google Scholar]
  118. 118.
    Kronenberg HM. 2003. Developmental regulation of the growth plate. Nature 423:332–36
    [Google Scholar]
  119. 119.
    Usui M, Xing L, Drissi H, Zuscik M, O'Keefe R et al. 2008. Murine and chicken chondrocytes regulate osteoclastogenesis by producing RANKL in response to BMP2. J. Bone Miner. Res. 23:314–25
    [Google Scholar]
  120. 120.
    Roach HI. 1992. Trans-differentiation of hypertrophic chondrocytes into cells capable of producing a mineralized bone matrix. Bone Miner. 19:1–20
    [Google Scholar]
  121. 121.
    Zhou X, von der Mark K, Henry S, Norton W, Adams H, de Crombrugghe B. 2014. Chondrocytes transdifferentiate into osteoblasts in endochondral bone during development, postnatal growth and fracture healing in mice. PLOS Genet. 10:e1004820
    [Google Scholar]
  122. 122.
    MacLeod RS, Cawley KM, Gubrij I, Nookaew I, Onal M, O'Brien CA. 2019. Effective CRISPR interference of an endogenous gene via a single transgene in mice. Sci. Rep. 9:17312
    [Google Scholar]
  123. 123.
    Toraldo G, Roggia C, Qian WP, Pacifici R, Weitzmann MN. 2003. IL-7 induces bone loss in vivo by induction of receptor activator of nuclear factor κB ligand and tumor necrosis factor α from T cells. PNAS 100:125–30
    [Google Scholar]
  124. 124.
    Eghbali-Fatourechi G, Khosla S, Sanyal A, Boyle WJ, Lacey DL, Riggs BL. 2003. Role of RANK ligand in mediating increased bone resorption in early postmenopausal women. J. Clin. Investig. 111:1221–30
    [Google Scholar]
  125. 125.
    Danks L, Komatsu N, Guerrini MM, Sawa S, Armaka M et al. 2016. RANKL expressed on synovial fibroblasts is primarily responsible for bone erosions during joint inflammation. Ann. Rheum. Dis. 75:1187–95
    [Google Scholar]
  126. 126.
    Lacey DL, Timms E, Tan HL, Kelley MJ, Dunstan CR et al. 1998. Osteoprotegerin ligand is a cytokine that regulates osteoclast differentiation and activation. Cell 93:165–76
    [Google Scholar]
  127. 127.
    Takahashi N, Akatsu T, Udagawa N, Sasaki T, Yamaguchi A et al. 1988. Osteoblastic cells are involved in osteoclast formation. Endocrinol. 123:2600–2
    [Google Scholar]
  128. 128.
    Xiong J, Cawley K, Piemontese M, Fujiwara Y, Zhao H et al. 2018. Soluble RANKL contributes to osteoclast formation in adult mice but not ovariectomy-induced bone loss. Nat. Commun. 9:2909
    [Google Scholar]
  129. 129.
    Asano T, Okamoto K, Nakai Y, Tsutsumi M, Muro R et al. 2019. Soluble RANKL is physiologically dispensable but accelerates tumour metastasis to bone. Nat. Metab. 1:868–75
    [Google Scholar]
  130. 130.
    Simonet WS, Lacey DL, Dunstan CR, Kelley M, Chang MS et al. 1997. Osteoprotegerin: a novel secreted protein involved in the regulation of bone density. Cell 89:309–19
    [Google Scholar]
  131. 131.
    Theoleyre S, Wittrant Y, Tat SK, Fortun Y, Redini F, Heymann D. 2004. The molecular triad OPG/RANK/RANKL: involvement in the orchestration of pathophysiological bone remodeling. Cytokine Growth Factor Rev. 15:457–75
    [Google Scholar]
  132. 132.
    Udagawa N, Koide M, Nakamura M, Nakamichi Y, Yamashita T et al. 2021. Osteoclast differentiation by RANKL and OPG signaling pathways. J. Bone Miner. Metab. 39:19–26
    [Google Scholar]
  133. 133.
    Tsukasaki M, Asano T, Muro R, Huynh NC, Komatsu N et al. 2020. OPG production matters where it happened. Cell Rep. 32:108124
    [Google Scholar]
  134. 134.
    Cawley KM, Bustamante-Gomez NC, Guha AG, MacLeod RS, Xiong J et al. 2020. Local production of osteoprotegerin by osteoblasts suppresses bone resorption. Cell Rep. 32:108052
    [Google Scholar]
  135. 135.
    Li M, Xu D. 2020. Antiresorptive activity of osteoprotegerin requires an intact heparan sulfate-binding site. PNAS 117:17187–94
    [Google Scholar]
  136. 136.
    Miller PD, Bolognese MA, Lewiecki EM, McClung MR, Ding B et al. 2008. Effect of denosumab on bone density and turnover in postmenopausal women with low bone mass after long-term continued, discontinued, and restarting of therapy: a randomized blinded phase 2 clinical trial. Bone 43:222–29
    [Google Scholar]
  137. 137.
    Bone HG, Bolognese MA, Yuen CK, Kendler DL, Miller PD et al. 2011. Effects of denosumab treatment and discontinuation on bone mineral density and bone turnover markers in postmenopausal women with low bone mass. J. Clin. Endocrinol. Metab. 96:972–80
    [Google Scholar]
  138. 138.
    Dempster DW, Brown JP, Fahrleitner-Pammer A, Kendler D, Rizzo S et al. 2018. Effects of long-term denosumab on bone histomorphometry and mineralization in women with postmenopausal osteoporosis. J. Clin. Endocrinol. Metab. 103:2498–509
    [Google Scholar]
  139. 139.
    Weinstein RS. 2011. Clinical practice. Glucocorticoid-induced bone disease. N. Engl. J. Med. 365:62–70
    [Google Scholar]
  140. 140.
    Henneicke H, Herrmann M, Kalak R, Brennan-Speranza TC, Heinevetter U et al. 2011. Corticosterone selectively targets endo-cortical surfaces by an osteoblast-dependent mechanism. Bone 49:733–42
    [Google Scholar]
  141. 141.
    Piemontese M, Xiong J, Fujiwara Y, Thostenson JD, O'Brien CA. 2016. Cortical bone loss caused by glucocorticoid excess requires RANKL production by osteocytes and is associated with reduced OPG expression in mice. Am. J. Physiol. Endocrinol. Metab. 311:E587–93
    [Google Scholar]
  142. 142.
    Weinstein RS, Jilka RL, Parfitt AM, Manolagas SC. 1998. Inhibition of osteoblastogenesis and promotion of apoptosis of osteoblasts and osteocytes by glucocorticoids. Potential mechanisms of their deleterious effects on bone. J. Clin. Investig. 102:274–82
    [Google Scholar]
  143. 143.
    Almeida M, Laurent MR, Dubois V, Claessens F, O'Brien CA et al. 2017. Estrogens and androgens in skeletal physiology and pathophysiology. Physiol. Rev. 97:135–87
    [Google Scholar]
  144. 144.
    Nakamura T, Imai Y, Matsumoto T, Sato S, Takeuchi K et al. 2007. Estrogen prevents bone loss via estrogen receptor α and induction of Fas ligand in osteoclasts. Cell 130:811–23
    [Google Scholar]
  145. 145.
    Martin-Millan M, Almeida M, Ambrogini E, Han L, Zhao H et al. 2010. The estrogen receptor-α in osteoclasts mediates the protective effects of estrogens on cancellous but not cortical bone. Mol. Endocrinol. 24:323–34
    [Google Scholar]
  146. 146.
    Bartell SM, Kim HN, Ambrogini E, Han L, Iyer S et al. 2014. FoxO proteins restrain osteoclastogenesis and bone resorption by attenuating H2O2 accumulation. Nat. Commun. 5:3773
    [Google Scholar]
  147. 147.
    Ha H, Kwak HB, Lee SW, Jin HM, Kim HM et al. 2004. Reactive oxygen species mediate RANK signaling in osteoclasts. Exp. Cell Res. 301:119–27
    [Google Scholar]
  148. 148.
    Almeida M, Iyer S, Martin-Millan M, Bartell SM, Han L et al. 2013. Estrogen receptor-α signaling in osteoblast progenitors stimulates cortical bone accrual. J. Clin. Investig. 123:394–404
    [Google Scholar]
  149. 149.
    Wu D, Cline-Smith A, Shashkova E, Perla A, Katyal A, Aurora R 2021. T-cell mediated inflammation in postmenopausal osteoporosis. Front. Immunol. 12:687551
    [Google Scholar]
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