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Osteoclasts—Key Players in Skeletal Health and Disease

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  • Authors: Deborah Veis Novack1,2, Gabriel Mbalaviele3
  • Editor: Siamon Gordon4
  • VIEW AFFILIATIONS HIDE AFFILIATIONS
    Affiliations: 1: Musculoskeletal Research Center, Division of Bone and Mineral Diseases, Department of Medicine; 2: Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110; 3: Musculoskeletal Research Center, Division of Bone and Mineral Diseases, Department of Medicine; 4: Oxford University, Oxford, United Kingdom
    • Source: microbiolspec June 2016 vol. 4 no. 3 doi:10.1128/microbiolspec.MCHD-0011-2015
  • Received 15 May 2015 Accepted 30 September 2015 Published 10 June 2016
  • Deborah Veis Novack, [email protected]; Gabriel Mbalaviele, [email protected]
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  • Abstract:

    The differentiation of osteoclasts (OCs) from early myeloid progenitors is a tightly regulated process that is modulated by a variety of mediators present in the bone microenvironment. Once generated, the function of mature OCs depends on cytoskeletal features controlled by an αβ-containing complex at the bone-apposed membrane and the secretion of protons and acid-protease cathepsin K. OCs also have important interactions with other cells in the bone microenvironment, including osteoblasts and immune cells. Dysregulation of OC differentiation and/or function can cause bone pathology. In fact, many components of OC differentiation and activation have been targeted therapeutically with great success. However, questions remain about the identity and plasticity of OC precursors and the interplay between essential networks that control OC fate. In this review, we summarize the key principles of OC biology and highlight recently uncovered mechanisms regulating OC development and function in homeostatic and disease states.

  • Citation: Novack D, Mbalaviele G. 2016. Osteoclasts—Key Players in Skeletal Health and Disease. Microbiol Spectrum 4(3):MCHD-0011-2015. doi:10.1128/microbiolspec.MCHD-0011-2015.

References

1. Mosaad YM. 2014. Hematopoietic stem cells: an overview. Transfus Apheresis Sci 51:68–82. [PubMed][CrossRef]
2. Demulder A, Takahashi S, Singer FR, Hosking DJ, Roodman GD. 1993. Abnormalities in osteoclast precursors and marrow accessory cells in Paget’s disease. Endocrinology 133:1978–1982. [PubMed]
3. Demulder A, Suggs SV, Zsebo KM, Scarcez T, Roodman GD. 1992. Effects of stem cell factor on osteoclast-like cell formation in long-term human marrow cultures. J Bone Miner Res 7:1337–1344. [PubMed][CrossRef]
4. Bonar SL, Brydges SD, Mueller JL, McGeough MD, Pena C, Chen D, Grimston SK, Hickman-Brecks CL, Ravindran S, McAlinden A, Novack DV, Kastner DL, Civitelli R, Hoffman HM, Mbalaviele G. 2012. Constitutively activated NLRP3 inflammasome causes inflammation and abnormal skeletal development in mice. PLoS One 7:e35979. doi:10.1371/journal.pone.0035979. [CrossRef]
5. Mediero A, Perez-Aso M, Cronstein BN. 2014. Activation of EPAC1/2 is essential for osteoclast formation by modulating NFκB nuclear translocation and actin cytoskeleton rearrangements. FASEB J 28:4901–4913. [PubMed][CrossRef]
6. Xing L, Boyce B. 2014. RANKL-based osteoclastogenic assays from murine bone marrow Cells, p 307–313. In Hilton MJ (ed), Skeletal Development and Repair, vol 1130. Humana Press, Totowa, NJ. [PubMed][CrossRef]
7. Mabilleau G, Pascaretti-Grizon F, Baslé MF, Chappard D. 2012. Depth and volume of resorption induced by osteoclasts generated in the presence of RANKL, TNF-alpha/IL-1 or LIGHT. Cytokine 57:294–299. [PubMed][CrossRef]
8. Li P, Schwarz EM, O’Keefe RJ, Ma L, Looney RJ, Ritchlin CT, Boyce BF, Xing L. 2004. Systemic tumor necrosis factor α mediates an increase in peripheral CD11b high osteoclast precursors in tumor necrosis factor α-transgenic mice. Arthritis Rheum 50:265–276. [PubMed][CrossRef]
9. Henriksen K, Karsdal M, Taylor A, Tosh D, Coxon F. 2012. Generation of human osteoclasts from peripheral blood, p 159–175. In Helfrich MH, Ralston SH (ed), Bone Research Protocols, vol 816. Humana Press, Totowa, NJ. [PubMed][CrossRef]
10. Bradley E, Oursler M. 2008. Osteoclast culture and resorption assays, p 19–35. In Westendorf J (ed), Osteoporosis, vol 455. Humana Press, Totowa, NJ. [PubMed][CrossRef]
11. Wang Y, Menendez A, Fong C, ElAlieh HZ, Chang W, Bikle DD. 2014. Ephrin B2/EphB4 mediates the actions of IGF-I signaling in regulating endochondral bone formation. J Bone Miner Res 29:1900–1913. [PubMed][CrossRef]
12. Hayman AR, Jones SJ, Boyde A, Foster D, Colledge WH, Carlton MB, Evans MJ, Cox TM. 1996. Mice lacking tartrate-resistant acid phosphatase (Acp 5) have disrupted endochondral ossification and mild osteopetrosis. Development 122:3151–3162. [PubMed]
13. Sago K, Teitelbaum SL, Venstrom K, Reichardt LF, Ross FP. 1999. The integrin α vβ 5 is expressed on avian osteoclast precursors and regulated by retinoic acid. J Bone Miner Res 14:32–38. [PubMed][CrossRef]
14. Saftig P, Hunziker E, Wehmeyer O, Jones S, Boyde A, Rommerskirch W, Moritz JD, Schu P, von Figura K. 1998. Impaired osteoclastic bone resorption leads to osteopetrosis in cathepsin-K-deficient mice. Proc Natl Acad Sci USA 95:13453–13458. [PubMed][CrossRef]
15. Gowen M, Lazner F, Dodds R, Kapadia R, Feild J, Tavaria M, Bertoncello I, Drake F, Zavarselk S, Tellis I, Hertzog P, Debouck C, Kola I. 1999. Cathepsin K knockout mice develop osteopetrosis due to a deficit in matrix degradation but not demineralization. J Bone Miner Res 14:1654–1663. [PubMed][CrossRef]
16. Hoff AO, Catala-Lehnen P, Thomas PM, Priemel M, Rueger JM, Nasonkin I, Bradley A, Hughes MR, Ordonez N, Cote GJ, Amling M, Gagel RF. 2002. Increased bone mass is an unexpected phenotype associated with deletion of the calcitonin gene. J Clin Invest 110:1849–1857. [PubMed][CrossRef]
17. Kim N, Takami M, Rho J, Josien R, Choi Y. 2002. A novel member of the leukocyte receptor complex regulates osteoclast differentiation. J Exp Med 195:201–209. [PubMed][CrossRef]
18. Sørensen MG, Henriksen K, Schaller S, Henriksen DB, Nielsen FC, Dziegiel MH, Karsdal MA. 2007. Characterization of osteoclasts derived from CD14 + monocytes isolated from peripheral blood. J Bone Miner Metab 25:36–45. [PubMed][CrossRef]
19. McHugh KP, Hodivala-Dilke K, Zheng MH, Namba N, Lam J, Novack D, Feng X, Ross FP, Hynes RO, Teitelbaum SL. 2000. Mice lacking β3 integrins are osteosclerotic because of dysfunctional osteoclasts. J Clin Invest 105:433–440. [PubMed][CrossRef]
20. Chen TH, Swarnkar G, Mbalaviele G, Abu-Amer Y. 2015. Myeloid lineage skewing due to exacerbated NF-κB signaling facilitates osteopenia in Scurfy mice. Cell Death Dis 6:e1723. doi:10.1038/cddis.2015.87. [PubMed][CrossRef]
21. Mbalaviele G, Jaiswal N, Meng A, Cheng L, Bos CV, Thiede M. 1999. Human mesenchymal stem cells promote human osteoclast differentiation from CD34 + bone marrow hematopoietic progenitors. Endocrinology 140:3736–3743. [CrossRef]
22. Matayoshi A, Brown C, DiPersio JF, Haug J, Abu-Amer Y, Liapis H, Kuestner R, Pacifici R. 1996. Human blood-mobilized hematopoietic precursors differentiate into osteoclasts in the absence of stromal cells. Proc Natl Acad Sci USA 93:10785–10790. [PubMed][CrossRef]
23. Muto A, Mizoguchi T, Udagawa N, Ito S, Kawahara I, Abiko Y, Arai A, Harada S, Kobayashi Y, Nakamichi Y, Penninger JM, Noguchi T, Takahashi N. 2011. Lineage-committed osteoclast precursors circulate in blood and settle down into bone. J Bone Miner Res 26:2978–2990. [PubMed][CrossRef]
24. Durand M, Komarova SV, Bhargava A, Trebec-Reynolds DP, Li K, Fiorino C, Maria O, Nabavi N, Manolson MF, Harrison RE, Dixon SJ, Sims SM, Mizianty MJ, Kurgan L, Haroun S, Boire G, de Fatima Lucena-Fernandes M, de Brum-Fernandes AJ. 2013. Monocytes from patients with osteoarthritis display increased osteoclastogenesis and bone resorption: the In Vitro Osteoclast Differentiation in Arthritis study. Arthritis Rheum 65:148–158. [PubMed][CrossRef]
25. Hemingway F, Cheng X, Knowles HJ, Estrada FM, Gordon S, Athanasou NA. 2011. In vitro generation of mature human osteoclasts. Calcif Tissue Int 89:389–395. [PubMed][CrossRef]
26. Lam J, Takeshita S, Barker JE, Kanagawa O, Ross FP, Teitelbaum SL. 2000. TNF-α induces osteoclastogenesis by direct stimulation of macrophages exposed to permissive levels of RANK ligand. J Clin Invest 106:1481–1488. [PubMed][CrossRef]
27. Charles JF, Hsu LY, Niemi EC, Weiss A, Aliprantis AO, Nakamura MC. 2012. Inflammatory arthritis increases mouse osteoclast precursors with myeloid suppressor function. J Clin Invest 122:4592–4605. [PubMed][CrossRef]
28. Jacome-Galarza CE, Lee S-K, Lorenzo JA, Aguila HL. 2013. Identification, characterization, and isolation of a common progenitor for osteoclasts, macrophages, and dendritic cells from murine bone marrow and periphery. J Bone Miner Res 28:1203–1213. [PubMed][CrossRef]
29. Jacquin C, Gran DE, Lee SK, Lorenzo JA, Aguila HL. 2006. Identification of multiple osteoclast precursor populations in murine bone marrow. J Bone Miner Res 21:67–77. [PubMed][CrossRef]
30. Takahashi N, Udagawa N, Tanaka S, Murakami H, Owan I, Tamura T, Suda T. 1994. Postmitotic osteoclast precursors are mononuclear cells which express macrophage-associated phenotypes. Dev Biol 163:212–221. [PubMed][CrossRef]
31. Park-Min KH, Lee EY, Moskowitz NK, Lim E, Lee SK, Lorenzo JA, Huang C, Melnick AM, Purdue PE, Goldring SR, Ivashkiv LB. 2013. Negative regulation of osteoclast precursor differentiation by CD11b and β2 integrin-B-cell lymphoma 6 signaling. J Bone Miner Res 28:135–149. [PubMed][CrossRef]
32. Zhuang J, Zhang J, Lwin ST, Edwards JR, Edwards CM, Mundy GR, Yang X. 2012. Osteoclasts in multiple myeloma are derived from Gr-1+CD11b+myeloid-derived suppressor cells. PLoS One 7:e48871. doi:10.1371/journal.pone.0048871. [PubMed][CrossRef]
33. Sawant A, Deshane J, Jules J, Lee CM, Harris BA, Feng X, Ponnazhagan S. 2013. Myeloid-derived suppressor cells function as novel osteoclast progenitors enhancing bone loss in breast cancer. Cancer Res 73:672–682. [PubMed][CrossRef]
34. Danilin S, Merkel AR, Johnson JR, Johnson RW, Edwards JR, Sterling JA. 2012. Myeloid-derived suppressor cells expand during breast cancer progression and promote tumor-induced bone destruction. OncoImmunology 1:1484–1494. [PubMed][CrossRef]
35. Yagi M, Miyamoto T, Sawatani Y, Iwamoto K, Hosogane N, Fujita N, Morita K, Ninomiya K, Suzuki T, Miyamoto K, Oike Y, Takeya M, Toyama Y, Suda T. 2005. DC-STAMP is essential for cell-cell fusion in osteoclasts and foreign body giant cells. J Exp Med 202:345–351. [PubMed][CrossRef]
36. Miyamoto H, Suzuki T, Miyauchi Y, Iwasaki R, Kobayashi T, Sato Y, Miyamoto K, Hoshi H, Hashimoto K, Yoshida S, Hao W, Mori T, Kanagawa H, Katsuyama E, Fujie A, Morioka H, Matsumoto M, Chiba K, Takeya M, Toyama Y, Miyamoto T. 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 27:1289–1297. [PubMed][CrossRef]
37. Mbalaviele G, Chen H, Boyce BF, Mundy GR, Yoneda T. 1995. The role of cadherin in the generation of multinucleated osteoclasts from mononuclear precursors in murine marrow. J Clin Invest 95:2757–2765. [PubMed][CrossRef]
38. Van den Bossche J, Malissen B, Mantovani A, De Baetselier P, Van Ginderachter JA. 2012. Regulation and function of the E-cadherin/catenin complex in cells of the monocyte-macrophage lineage and DCs. Blood 119:1623–1633. [PubMed][CrossRef]
39. Nakamura H, Nakashima T, Hayashi M, Izawa N, Yasui T, Aburatani H, Tanaka S, Takayanagi H. 2014. Global epigenomic analysis indicates protocadherin-7 activates osteoclastogenesis by promoting cell-cell fusion. Biochem Biophys Res Commun 455:305–311. [PubMed][CrossRef]
40. Ishizuka H, García-Palacios V, Lu G, Subler MA, Zhang H, Boykin CS, Choi SJ, Zhao L, Patrene K, Galson DL, Blair HC, Hadi TM, Windle JJ, Kurihara N, Roodman GD. 2011. ADAM8 enhances osteoclast precursor fusion and osteoclast formation in vitro and in vivo. J Bone Miner Res 26:169–181. [PubMed][CrossRef]
41. Ishii M, Egen JG, Klauschen F, Meier-Schellersheim M, Saeki Y, Vacher J, Proia RL, Germain RN. 2009. Sphingosine-1-phosphate mobilizes osteoclast precursors and regulates bone homeostasis. Nature 458:524–528. [PubMed][CrossRef]
42. Ishii M, Kikuta J, Shimazu Y, Meier-Schellersheim M, Germain RN. 2010. Chemorepulsion by blood S1P regulates osteoclast precursor mobilization and bone remodeling in vivo. J Exp Med 207:2793–2798. [PubMed][CrossRef]
43. Ishii M, Kikuta J. 2013. Sphingosine-1-phosphate signaling controlling osteoclasts and bone homeostasis. Biochim Biophys Acta 1831:223–227. [PubMed][CrossRef]
44. Shahnazari M, Chu V, Wronski TJ, Nissenson RA, Halloran BP. 2013. CXCL12/CXCR4 signaling in the osteoblast regulates the mesenchymal stem cell and osteoclast lineage populations. FASEB J 27:3505–3513. [PubMed][CrossRef]
45. Takahashi N, Akatsu T, Udagawa N, Sasaki T, Yamaguchi A, Moseley JM, Martin TJ, Suda T. 1988. Osteoblastic cells are involved in osteoclast formation. Endocrinology 123:2600–2602. [PubMed][CrossRef]
46. Udagawa N, Takahashi N, Akatsu T, Tanaka H, Sasaki T, Nishihara T, Koga T, Martin TJ, Suda T. 1990. Origin of osteoclasts: mature monocytes and macrophages are capable of differentiating into osteoclasts under a suitable microenvironment prepared by bone marrow-derived stromal cells. Proc Natl Acad Sci USA 87:7260–7264. [PubMed][CrossRef]
47. Wiktor-Jedrzejczak WW, Ahmed A, Szczylik C, Skelly RR. 1982. Hematological characterization of congenital osteopetrosis in op/op mouse. Possible mechanism for abnormal macrophage differentiation. J Exp Med 156:1516–1527. [PubMed][CrossRef]
48. Yoshida H, Hayashi SI, Kunisada T, Ogawa M, Nishikawa S, Okamura H, Sudo T, Shultz LD, Nishikawa SI. 1990. The murine mutation osteopetrosis is in the coding region of the macrophage colony stimulating factor gene. Nature 345:442–444. [PubMed][CrossRef]
49. Felix R, Cecchini MG, Hofstetter W, Elford PR, Stutzer A, Fleisch H. 1990. Impairment of macrophage colony-stimulating factor production and lack of resident bone marrow macrophages in the osteopetrotic op/op mouse. J Bone Miner Res 5:781–789. [PubMed][CrossRef]
50. Stanley ER, Chitu V. 2014. CSF-1 receptor signaling in myeloid cells. Cold Spring Harb Perspect Biol 6:a021857. doi:10.1101/cshperspect.a021857. [PubMed]
51. Otero K, Turnbull IR, Poliani PL, Vermi W, Cerutti E, Aoshi T, Tassi I, Takai T, Stanley SL, Miller M, Shaw AS, Colonna M. 2009. Macrophage colony-stimulating factor induces the proliferation and survival of macrophages via a pathway involving DAP12 and β-catenin. Nat Immunol 10:734–743. [PubMed][CrossRef]
52. Glantschnig H, Fisher JE, Wesolowski G, Rodan GA, Reszka AA. 2003. M-CSF, TNFα and RANK ligand promote osteoclast survival by signaling through mTOR/S6 kinase. Cell Death Differ 10:1165–1177. [PubMed][CrossRef]
53. Zamani A, Decker C, Cremasco V, Hughes L, Novack DV, Faccio R. 2015. Diacylglycerol kinase ζ (DGKζ) is a critical regulator of bone homeostasis via modulation of c-Fos levels in osteoclasts. J Bone Miner Res 30:1852–1863. [PubMed][CrossRef]
54. Baud’Huin M, Renault R, Charrier C, Riet A, Moreau A, Brion R, Gouin F, Duplomb L, Heymann D. 2010. Interleukin-34 is expressed by giant cell tumours of bone and plays a key role in RANKL-induced osteoclastogenesis. J Pathol 221:77–86. [PubMed][CrossRef]
55. Chen Z, Buki K, Vääräniemi J, Gu G, Väänänen HK. 2011. The critical role of IL-34 in osteoclastogenesis. PLoS One 6:e18689. doi:10.1371/journal.pone.0018689. [PubMed][CrossRef]
56. Li J, Chen K, Zhu L, Pollard JW. 2006. Conditional deletion of the colony stimulating factor-1 receptor ( c-fms proto-oncogene) in mice. Genesis 44:328–335. [PubMed][CrossRef]
57. Lee MS, Kim HS, Yeon JT, Choi SW, Chun CH, Kwak HB, Oh J. 2009. GM-CSF regulates fusion of mononuclear osteoclasts into bone-resorbing osteoclasts by activating the Ras/ERK pathway. J Immunol 183:3390–3399. [PubMed][CrossRef]
58. Niida S, Kaku M, Amano H, Yoshida H, Kataoka H, Nishikawa S, Tanne K, Maeda N, Nishikawa SI, Kodama H. 1999. Vascular endothelial growth factor can substitute for macrophage colony-stimulating factor in the support of osteoclastic bone resorption. J Exp Med 190:293–298. [PubMed][CrossRef]
59. Nakagawa M, Kaneda T, Arakawa T, Morita S, Sato T, Yomada T, Hanada K, Kumegawa M, Hakeda Y. 2000. Vascular endothelial growth factor (VEGF) directly enhances osteoclastic bone resorption and survival of mature osteoclasts. FEBS Lett 473:161–164. [CrossRef]
60. Adamopoulos IE, Xia Z, Lau YS, Athanasou NA. 2006. Hepatocyte growth factor can substitute for M-CSF to support osteoclastogenesis. Biochem Biophys Res Commun 350:478–483. [PubMed][CrossRef]
61. Lacey DL, Timms E, Tan HL, Kelley MJ, Dunstan CR, Burgess T, Elliott R, Colombero A, Elliott G, Scully S, Hsu H, Sullivan J, Hawkins N, Davy E, Capparelli C, Eli A, Qian YX, Kaufman S, Sarosi I, Shalhoub V, Senaldi G, Guo J, Delaney J, Boyle WJ. 1998. Osteoprotegerin ligand is a cytokine that regulates osteoclast differentiation and activation. Cell 93:165–176. [CrossRef]
62. Yasuda H, Shima N, Nakagawa N, Yamaguchi K, Kinosaki M, Mochizuki S, Tomoyasu A, Yano K, Goto M, Murakami A, Tsuda E, Morinaga T, Higashio K, Udagawa N, Takahashi N, Suda T. 1998. 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. [PubMed][CrossRef]
63. Kong YY, Yoshida H, Sarosi I, Tan HL, Timms E, Capparelli C, Morony S, Oliveira-dos-Santos AJ, Van G, Itie A, Khoo W, Wakeham A, Dunstan CR, Lacey DL, Mak TW, Boyle WJ, Penninger JM. 1999. OPGL is a key regulator of osteoclastogenesis, lymphocyte development and lymph-node organogenesis. Nature 397:315–323. [PubMed][CrossRef]
64. Bucay N, Sarosi I, Dunstan CR, Morony S, Tarpley J, Capparelli C, Scully S, Tan HL, Xu W, Lacey DL, Boyle WJ, Simonet WS. 1998. osteoprotegerin-deficient mice develop early onset osteoporosis and arterial calcification. Genes Dev 12:1260–1268. [PubMed][CrossRef]
65. Whyte MP, Tau C, McAlister WH, Zhang X, Novack DV, Preliasco V, Santini-Araujo E, Mumm S. 2014. Juvenile Paget’s disease with heterozygous duplication within TNFRSF11A encoding RANK. Bone 68:153–161. [PubMed][CrossRef]
66. Hughes AE, Ralston SH, Marken J, Bell C, MacPherson H, Wallace RG, van Hul W, Whyte MP, Nakatsuka K, Hovy L, Anderson DM. 2000. Mutations in TNFRSF11A, affecting the signal peptide of RANK, cause familial expansile osteolysis. Nat Genet 24:45–48. [PubMed][CrossRef]
67. Novack DV, Teitelbaum SL. 2008. The osteoclast: friend or foe? Annu Rev Pathol 3:457–484. [PubMed][CrossRef]
68. Smink JJ, Bégay V, Schoenmaker T, Sterneck E, de Vries TJ, Leutz A. 2009. Transcription factor C/EBPβ isoform ratio regulates osteoclastogenesis through MafB. EMBO J 28:1769–1781. [PubMed][CrossRef]
69. Smink J, Tunn PU, Leutz A. 2012. Rapamycin inhibits osteoclast formation in giant cell tumor of bone through the C/EBPβ-MafB axis. J Mol Med Berl 90:25–30. [PubMed][CrossRef]
70. Takayanagi H, Kim S, Koga T, Nishina H, Isshiki M, Yoshida H, Saiura A, Isobe M, Yokochi T, Inoue J, Wagner EF, Mak TW, Kodama T, Taniguchi T. 2002. Induction and activation of the transcription factor NFATc1 (NFAT2) integrate RANKL signaling in terminal differentiation of osteoclasts. Dev Cell 3:889–901. [PubMed][CrossRef]
71. Mao D, Epple H, Uthgenannt B, Novack DV, Faccio R. 2006. PLCγ2 regulates osteoclastogenesis via its interaction with ITAM proteins and GAB2. J Clin Invest 116:2869–2879. [PubMed][CrossRef]
72. Alhawagri M, Yamanaka Y, Ballard D, Oltz E, Abu-Amer Y. 2012. Lysine392, a K63-linked ubiquitination site in NEMO, mediates inflammatory osteoclastogenesis and osteolysis. J Orthop Res 30:554–560. [PubMed][CrossRef]
73. Bronisz A, Carey HA, Godlewski J, Sif S, Ostrowski MC, Sharma SM. 2014. The multifunctional protein fused in sarcoma (FUS) is a coactivator of microphthalmia-associated transcription factor (MITF). J Biol Chem 289:326–334. [PubMed][CrossRef]
74. Yasui T, Hirose J, Aburatani H, Tanaka S. 2011. Epigenetic regulation of osteoclast differentiation. Ann N Y Acad Sci 1240:7–13. [PubMed][CrossRef]
75. Kim JH, Kim N. 2014. Regulation of NFATc1 in osteoclast differentiation. J Bone Metab 21:233–241. [PubMed][CrossRef]
76. Mizoguchi F, Izu Y, Hayata T, Hemmi H, Nakashima K, Nakamura T, Kato S, Miyasaka N, Ezura Y, Noda M. 2010. Osteoclast-specific Dicer gene deficiency suppresses osteoclastic bone resorption. J Cell Biochem 109:866–875. [PubMed]
77. Nishikawa K, Iwamoto Y, Kobayashi Y, Katsuoka F, Kawaguchi S, Tsujita T, Nakamura T, Kato S, Yamamoto M, Takayanagi H, Ishii M. 2015. DNA methyltransferase 3a regulates osteoclast differentiation by coupling to an S-adenosylmethionine-producing metabolic pathway. Nat Med 21:281–287. [CrossRef]
78. 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 26:2665–2671. [PubMed][CrossRef]
79. Park-Min KH, Lim E, Lee MJ, Park SH, Giannopoulou E, Yarilina A, van der Meulen M, Zhao B, Smithers N, Witherington J, Lee K, Tak PP, Prinjha RK, Ivashkiv LB. 2014. Inhibition of osteoclastogenesis and inflammatory bone resorption by targeting BET proteins and epigenetic regulation. Nat Commun 5:5418. doi:10.1038/ncomms6418. [PubMed][CrossRef]
80. Shakibaei M, Buhrmann C, Mobasheri A. 2011. Resveratrol-mediated SIRT-1 interactions with p300 modulate receptor activator of NF-κB ligand (RANKL) activation of NF-κB signaling and inhibit osteoclastogenesis in bone-derived cells. J Biol Chem 286:11492–11505. [PubMed][CrossRef]
81. Hah YS, Cheon YH, Lim HS, Cho HY, Park BH, Ka SO, Lee YR, Jeong DW, Kim HO, Han MK, Lee SI. 2014. Myeloid deletion of SIRT1 aggravates serum transfer arthritis in mice via nuclear factor-κB activation. PLoS One 9:e87733. doi:10.1371/journal.pone.0087733. [CrossRef]
82. Zou W, Reeve JL, Liu Y, Teitelbaum SL, Ross FP. 2008. DAP12 couples c-Fms activation to the osteoclast cytoskeleton by recruitment of Syk. Mol Cell 31:422–431. [PubMed][CrossRef]
83. Mócsai A, Humphrey MB, Van Ziffle JAG, Hu Y, Burghardt A, Spusta SC, Majumdar S, Lanier LL, Lowell CA, Nakamura MC. 2004. The immunomodulatory adapter proteins DAP12 and Fc receptor γ-chain (FcRγ) regulate development of functional osteoclasts through the Syk tyrosine kinase. Proc Natl Acad Sci USA 101:6158–6163. [PubMed][CrossRef]
84. Koga T, Inui M, Inoue K, Kim S, Suematsu A, Kobayashi E, Iwata T, Ohnishi H, Matozaki T, Kodama T, Taniguchi T, Takayanagi H, Takai T. 2004. Costimulatory signals mediated by the ITAM motif cooperate with RANKL for bone homeostasis. Nature 428:758–763. [PubMed][CrossRef]
85. Wu Y, Torchia J, Yao W, Lane NE, Lanier LL, Nakamura MC, Humphrey MB. 2007. Bone microenvironment specific roles of ITAM adapter signaling during bone remodeling induced by acute estrogen-deficiency. PLoS One 2:e586. doi:10.1371/journal.pone.0000586. [CrossRef]
86. 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 Invest 124:5057–5073. [PubMed][CrossRef]
87. Zou W, Teitelbaum SL. 2015. Absence of Dap12 and the αvβ3 integrin causes severe osteopetrosis. J Cell Biol 208:125–136. [PubMed][CrossRef]
88. Li Y, Li A, Strait K, Zhang H, Nanes MS, Weitzmann MN. 2007. Endogenous TNFα lowers maximum peak bone mass and inhibits osteoblastic Smad activation through NF-κB. J Bone Miner Res 22:646–655. [PubMed][CrossRef]
89. Onal M, Xiong J, Chen X, Thostenson JD, Almeida M, Manolagas SC, O’Brien CA. 2012. Receptor activator of nuclear factor κB ligand (RANKL) protein expression by B lymphocytes contributes to ovariectomy-induced bone loss. J Biol Chem 287:29851–29860. [PubMed][CrossRef]
90. Kong YY, Feige U, Sarosi I, Bolon B, Tafuri A, Morony S, Capparelli C, Li J, Elliott R, McCabe S, Wong T, Campagnuolo G, Moran E, Bogoch ER, Van G, Nguyen LT, Ohashi PS, Lacey DL, Fish E, Boyle WJ, Penninger JM. 1999. Activated T cells regulate bone loss and joint destruction in adjuvant arthritis through osteoprotegerin ligand. Nature 402:304–309. [PubMed][CrossRef]
91. Weitzmann MN, Cenci S, Rifas L, Haug J, Dipersio J, Pacifici R. 2001. T cell activation induces human osteoclast formation via receptor activator of nuclear factor κB ligand-dependent and -independent mechanisms. J Bone Miner Res 16:328–337. [PubMed][CrossRef]
92. Horwood NJ, Kartsogiannis V, Quinn JM, Romas E, Martin TJ, Gillespie MT. 1999. Activated T lymphocytes support osteoclast formation in vitro. Biochem Biophys Res Commun 265:144–150. [PubMed][CrossRef]
93. Lee SK, Kadono Y, Okada F, Jacquin C, Koczon-Jaremko B, Gronowicz G, Adams DJ, Aguila HL, Choi Y, Lorenzo JA. 2006. T lymphocyte-deficient mice lose trabecular bone mass with ovariectomy. J Bone Miner Res 21:1704–1712. [PubMed][CrossRef]
94. 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. Proc Natl Acad Sci USA 100:125–130. [PubMed][CrossRef]
95. Li Y, Li A, Yang X, Weitzmann MN. 2007. Ovariectomy-induced bone loss occurs independently of B cells. J Cell Biochem 100:1370–1375. [PubMed][CrossRef]
96. Li Y, Toraldo G, Li A, Yang X, Zhang H, Qian W-P, Weitzmann MN. 2007. B cells and T cells are critical for the preservation of bone homeostasis and attainment of peak bone mass in vivo. Blood 109:3839–3848. [PubMed][CrossRef]
97. Zaiss MM, Axmann R, Zwerina J, Polzer K, Gückel E, Skapenko A, Schulze-Koops H, Horwood N, Cope A, Schett G. 2007. Treg cells suppress osteoclast formation: a new link between the immune system and bone. Arthritis Rheum 56:4104–4112. [PubMed][CrossRef]
98. Kelchtermans H, Geboes L, Mitera T, Huskens D, Leclercq G, Matthys P. 2009. Activated CD4 +CD25 + regulatory T cells inhibit osteoclastogenesis and collagen-induced arthritis. Ann Rheum Dis 68:744–750. [PubMed][CrossRef]
99. Zaiss MM, Sarter K, Hess A, Engelke K, Böhm C, Nimmerjahn F, Voll R, Schett G, David JP. 2010. Increased bone density and resistance to ovariectomy-induced bone loss in FoxP3-transgenic mice based on impaired osteoclast differentiation. Arthritis Rheum 62:2328–2338. [PubMed][CrossRef]
100. Luo CY, Wang L, Sun C, Li DJ. 2011. Estrogen enhances the functions of CD4 +CD25 +Foxp3 + regulatory T cells that suppress osteoclast differentiation and bone resorption in vitro. Cell Mol Immunol 8:50–58. [PubMed][CrossRef]
101. Kiesel JR, Buchwald ZS, Aurora R. 2009. Cross-presentation by osteoclasts induces FoxP3 in CD8 + T cells. J Immunol 182:5477–5487. [PubMed][CrossRef]
102. Buchwald ZS, Kiesel JR, Yang C, DiPaolo R, Novack DV, Aurora R. 2013. Osteoclast-induced Foxp3 + CD8 T-cells limit bone loss in mice. Bone 56:163–173. [PubMed][CrossRef]
103. Buchwald ZS, Yang C, Nellore S, Shashkova EV, Davis JL, Cline A, Ko J, Novack DV, DiPaolo R, Aurora R. 2015. A bone anabolic effect of RANKL in a murine model of osteoporosis mediated through FoxP3 + CD8 T cells. J Bone Miner Res 30:1508–1522. [PubMed][CrossRef]
104. Grassi F, Manferdini C, Cattini L, Piacentini A, Gabusi E, Facchini A, Lisignoli G. 2011. T cell suppression by osteoclasts in vitro. J Cell Physiol 226:982–990. [PubMed][CrossRef]
105. Li H, Hong S, Qian J, Zheng Y, Yang J, Yi Q. 2010. Cross talk between the bone and immune systems: osteoclasts function as antigen-presenting cells and activate CD4 + and CD8 + T cells. Blood 116:210–217. [PubMed][CrossRef]
106. Li H, Lu Y, Qian J, Zheng Y, Zhang M, Bi E, He J, Liu Z, Xu J, Gao JY, Yi Q. 2014. Human osteoclasts are inducible immunosuppressive cells in response to T cell-derived IFN-γ and CD40 ligand in vitro. J Bone Miner Res 29:2666–2675. [PubMed][CrossRef]
107. McHugh KP, Hodivala-Dilke K, Zheng MH, Namba N, Lam J, Novack D, Feng X, Ross FP, Hynes RO, Teitelbaum SL. 2000. Mice lacking β3 integrins are osteosclerotic because of dysfunctional osteoclasts. J Clin Invest 105:433–440. [PubMed][CrossRef]
108. DeSelm CJ, Miller BC, Zou W, Beatty WL, van Meel E, Takahata Y, Klumperman J, Tooze SA, Teitelbaum SL, Virgin HW. 2011. Autophagy proteins regulate the secretory component of osteoclastic bone resorption. Dev Cell 21:966–974. [PubMed][CrossRef]
109. Zou W, Izawa T, Zhu T, Chappel J, Otero K, Monkley SJ, Critchley DR, Petrich BG, Morozov A, Ginsberg MH, Teitelbaum SL. 2013. Talin1 and Rap1 are critical for osteoclast function. Mol Cell Biol 33:830–844. [PubMed][CrossRef]
110. Fukunaga T, Zou W, Warren JT, Teitelbaum SL. 2014. Vinculin regulates osteoclast function. J Biol Chem 289:13554–13564. [PubMed][CrossRef]
111. Schmidt S, Nakchbandi I, Ruppert R, Kawelke N, Hess MW, Pfaller K, Jurdic P, Fässler R, Moser M. 2011. Kindlin-3-mediated signaling from multiple integrin classes is required for osteoclast-mediated bone resorption. J Cell Biol 192:883–897. [PubMed][CrossRef]
112. Krits I, Wysolmerski RB, Holliday LS, Lee BS. 2002. Differential localization of myosin II isoforms in resting and activated osteoclasts. Calcif Tissue Int 71:530–538. [PubMed][CrossRef]
113. Zou W, DeSelm CJ, Broekelmann TJ, Mecham RP, Vande Pol S, Choi K, Teitelbaum SL. 2012. Paxillin contracts the osteoclast cytoskeleton. J Bone Miner Res 27:2490–2500. [PubMed][CrossRef]
114. Faccio R, Teitelbaum SL, Fujikawa K, Chappel J, Zallone A, Tybulewicz VL, Ross FP, Swat W. 2005. Vav3 regulates osteoclast function and bone mass. Nat Med 11:284–290. [PubMed][CrossRef]
115. Croke M, Ross FP, Korhonen M, Williams DA, Zou W, Teitelbaum SL. 2011. Rac deletion in osteoclasts causes severe osteopetrosis. J Cell Sci 124:3811–3821. [PubMed][CrossRef]
116. Zou W, Croke M, Fukunaga T, Broekelmann TJ, Mecham RP, Teitelbaum SL. 2013. Zap70 inhibits Syk-mediated osteoclast function. J Cell Biochem 114:1871–1878. [PubMed][CrossRef]
117. Soriano P, Montgomery C, Geske R, Bradley A. 1991. Targeted disruption of the c- src proto-oncogene leads to osteopetrosis in mice. Cell 64:693–702. [PubMed][CrossRef]
118. Zou W, Kitaura H, Reeve J, Long F, Tybulewicz VLJ, Shattil SJ, Ginsberg MH, Ross FP, Teitelbaum SL. 2007. Syk, c-Src, the αvβ3 integrin, and ITAM immunoreceptors, in concert, regulate osteoclastic bone resorption. J Cell Biol 176:877–888. [PubMed][CrossRef]
119. Baron R, Neff L, Louvard D, Courtoy PJ. 1985. Cell-mediated extracellular acidification and bone resorption: evidence for a low pH in resorbing lacunae and localization of a 100-kD lysosomal membrane protein at the osteoclast ruffled border. J Cell Biol 101:2210–2222. [PubMed][CrossRef]
120. Vaes G. 1968. On the mechanisms of bone resorption: the action of parathyroid hormone on the excretion and synthesis of lysosomal enzymes and on the extracellular release of acid by bone cells. J Cell Biol 39:676–697. [PubMed][CrossRef]
121. Gay CV, Schraer H, Anderson RE, Cao H. 1984. Current studies on the location and function of carbonic anhydrase in osteoclasts. Ann N Y Acad Sci 429:473–478. [PubMed][CrossRef]
122. Baron R, Neff L, Brown W, Courtoy PJ, Louvard D, Farquhar MG. 1988. Polarized secretion of lysosomal enzymes: co-distribution of cation-independent mannose-6-phosphate receptors and lysosomal enzymes along the osteoclast exocytic pathway. J Cell Biol 106:1863–1872. [PubMed][CrossRef]
123. Sobacchi C, Schulz A, Coxon FP, Villa A, Helfrich MH. 2013. Osteopetrosis: genetics, treatment and new insights into osteoclast function. Nat Rev Endocrinol 9:522–536. [PubMed][CrossRef]
124. Van Wesenbeeck L, Odgren PR, Coxon FP, Frattini A, Moens P, Perdu B, MacKay CA, Van Hul E, Timmermans JP, Vanhoenacker F, Jacobs R, Peruzzi B, Teti A, Helfrich MH, Rogers MJ, Villa A, Van Hul W. 2007. Involvement of PLEKHM1 in osteoclastic vesicular transport and osteopetrosis in incisors absent rats and humans. J Clin Invest 117:919–930. [PubMed][CrossRef]
125. Ye S, Fowler TW, Pavlos NJ, Ng PY, Liang K, Feng Y, Zheng M, Kurten R, Manolagas SC, Zhao H. 2011. LIS1 regulates osteoclast formation and function through its interactions with dynein/dynactin and Plekhm1. PLoS One 6:e27285. doi:10.1371/journal.pone.0027285. [PubMed][CrossRef]
126. Fujita Y, Nakata K, Yasui N, Matsui Y, Kataoka E, Hiroshima K, Shiba RI, Ochi T. 2000. Novel mutations of the cathepsin K gene in patients with pycnodysostosis and their characterization. J Clin Endocrinol Metab 85:425–431. [PubMed][CrossRef]
127. Andersen TL, del Carmen Ovejero M, Kirkegaard T, Lenhard T, Foged NT, Delaissé JM. 2004. A scrutiny of matrix metalloproteinases in osteoclasts: evidence for heterogeneity and for the presence of MMPs synthesized by other cells. Bone 35:1107–1119. [PubMed][CrossRef]
128. Mosig RA, Dowling O, DiFeo A, Ramirez MC, Parker IC, Abe E, Diouri J, Aqeel AA, Wylie JD, Oblander SA, Madri J, Bianco P, Apte SS, Zaidi M, Doty SB, Majeska RJ, Schaffler MB, Martignetti JA. 2007. Loss of MMP-2 disrupts skeletal and craniofacial development and results in decreased bone mineralization, joint erosion and defects in osteoblast and osteoclast growth. Hum Mol Genet 16:1113–1123. [PubMed][CrossRef]
129. Nesbitt SA, Horton MA. 1997. Trafficking of matrix collagens through bone-resorbing osteoclasts. Science 276:266–269. [PubMed][CrossRef]
130. Salo J, Lehenkari P, Mulari M, Metsikkö K, Väänänen HK. 1997. Removal of osteoclast bone resorption products by transcytosis. Science 276:270–273. [PubMed][CrossRef]
131. Kawana K, Takahashi M, Hoshino H, Kushida K. 2002. Comparison of serum and urinary C-terminal telopeptide of type I collagen in aging, menopause and osteoporosis. Clin Chim Acta 316:109–115. [PubMed][CrossRef]
132. Qu C, Bonar SL, Hickman-Brecks CL, Abu-Amer S, McGeough MD, Peña CA, Broderick L, Yang C, Grimston SK, Kading J, Abu-Amer Y, Novack DV, Hoffman HM, Civitelli R, Mbalaviele G. 2015. NLRP3 mediates osteolysis through inflammation-dependent and -independent mechanisms. FASEB J 29:1269–1279. [PubMed][CrossRef]
133. Burton L, Paget D, Binder NB, Bohnert K, Nestor BJ, Sculco TP, Santambrogio L, Ross FP, Goldring SR, Purdue PE. 2013. Orthopedic wear debris mediated inflammatory osteolysis is mediated in part by NALP3 inflammasome activation. J Orthop Res 31:73–80. [PubMed][CrossRef]
134. Youm YH, Grant RW, McCabe LR, Albarado DC, Nguyen KY, Ravussin A, Pistell P, Newman S, Carter R, Laque A, Münzberg H, Rosen CJ, Ingram DK, Salbaum JM, Dixit VD. 2013. Canonical Nlrp3 inflammasome links systemic low-grade inflammation to functional decline in aging. Cell Metab 18:519–532. [PubMed][CrossRef]
135. Scianaro R, Insalaco A, Bracci Laudiero L, De Vito R, Pezzullo M, Teti A, De Benedetti F, Prencipe G. 2014. Deregulation of the IL-1β axis in chronic recurrent multifocal osteomyelitis. Pediatr Rheumatol Online J 12:30–30. [PubMed][CrossRef]
136. Tang Y, Wu X, Lei W, Pang L, Wan C, Shi Z, Zhao L, Nagy TR, Peng X, Hu J, Feng X, Van Hul W, Wan M, Cao X. 2009. TGF-β1-induced migration of bone mesenchymal stem cells couples bone resorption with formation. Nat Med 15:757–765. [PubMed][CrossRef]
137. Xian L, Wu X, Pang L, Lou M, Rosen CJ, Qiu T, Crane J, Frassica F, Zhang L, Rodriguez JP, Jia X, Yakar S, Xuan S, Efstratiadis A, Wan M, Cao X. 2012. Matrix IGF-1 maintains bone mass by activation of mTOR in mesenchymal stem cells. Nat Med 18:1095–1101. [PubMed][CrossRef]
138. Ota K, Quint P, Ruan M, Pederson L, Westendorf JJ, Khosla S, Oursler MJ. 2013. TGF-β induces Wnt10b in osteoclasts from female mice to enhance coupling to osteoblasts. Endocrinology 154:3745–3752. [PubMed][CrossRef]
139. Ota K, Quint P, Weivoda MM, Ruan M, Pederson L, Westendorf JJ, Khosla S, Oursler MJ. 2013. Transforming growth factor beta 1 induces CXCL16 and leukemia inhibitory factor expression in osteoclasts to modulate migration of osteoblast progenitors. Bone 57:68–75. [PubMed][CrossRef]
140. Lotinun S, Kiviranta R, Matsubara T, Alzate JA, Neff L, Lüth A, Koskivirta I, Kleuser B, Vacher J, Vuorio E, Horne WC, Baron R. 2013. Osteoclast-specific cathepsin K deletion stimulates S1P-dependent bone formation. J Clin Invest 123:666–681. [PubMed][CrossRef]
141. Takeshita S, Fumoto T, Matsuoka K, Park KA, Aburatani H, Kato S, Ito M, Ikeda K. 2013. Osteoclast-secreted CTHRC1 in the coupling of bone resorption to formation. J Clin Invest 123:3914–3924. [PubMed][CrossRef]
142. Negishi-Koga T, Shinohara M, Komatsu N, Bito H, Kodama T, Friedel RH, Takayanagi H. 2011. Suppression of bone formation by osteoclastic expression of semaphorin 4D. Nat Med 17:1473–1480. [PubMed][CrossRef]
143. Irie N, Takada Y, Watanabe Y, Matsuzaki Y, Naruse C, Asano M, Iwakura Y, Suda T, Matsuo K. 2009. Bidirectional signaling through ephrinA2-EphA2 enhances osteoclastogenesis and suppresses osteoblastogenesis. J Biol Chem 284:14637–14644. [PubMed][CrossRef]
144. Zhao C, Irie N, Takada Y, Shimoda K, Miyamoto T, Nishiwaki T, Suda T, Matsuo K. 2006. Bidirectional ephrinB2-EphB4 signaling controls bone homeostasis. Cell Metab 4:111–121. [PubMed][CrossRef]
145. Cauley JA. 2015. Estrogen and bone health in men and women. Steroids 99(Pt A) :11–15. [PubMed]
146. Manolagas SC, O’Brien CA, Almeida M. 2013. The role of estrogen and androgen receptors in bone health and disease. Nat Rev Endocrinol 9:699–712. [PubMed][CrossRef]
147. Andreopoulou P, Bockman RS. 2015. Management of postmenopausal osteoporosis. Annu Rev Med 66:329–342. [PubMed][CrossRef]
148. Franceschi C, Campisi J. 2014. Chronic inflammation (inflammaging) and its potential contribution to age-associated diseases. J Gerontol A Biol Sci Med Sci 69:S4–S9. [PubMed][CrossRef]
149. Sanguineti R, Puddu A, Mach F, Montecucco F, Viviani GL. 2014. Advanced glycation end products play adverse proinflammatory activities in osteoporosis. Mediators Inflamm 975872: doi:10.1155/2014/975872. [PubMed][CrossRef]
150. D’Amelio P, Grimaldi A, Di Bella S, Brianza SZ, Cristofaro MA, Tamone C, Giribaldi G, Ulliers D, Pescarmona GP, Isaia G. 2008. Estrogen deficiency increases osteoclastogenesis up-regulating T cells activity: a key mechanism in osteoporosis. Bone 43:92–100. [PubMed][CrossRef]
151. Cenci S, Weitzmann MN, Roggia C, Namba N, Novack D, Woodring J, Pacifici R. 2000. Estrogen deficiency induces bone loss by enhancing T-cell production of TNF-α. J Clin Invest 106:1229–1237. [PubMed][CrossRef]
152. Koenders MI, van den Berg WB. 2015. Novel therapeutic targets in rheumatoid arthritis. Trends Pharmacol Sci 36:189–195. [PubMed][CrossRef]
153. Tanaka T, Narazaki M, Kishimoto T. 2014. IL-6 in inflammation, immunity, and disease. Cold Spring Harb Perspect Biol 6:a016295. doi:10.1101/cshperspect.a016295. [PubMed][CrossRef]
154. van Staa TP, Geusens P, Bijlsma JW, Leufkens HG, Cooper C. 2006. Clinical assessment of the long-term risk of fracture in patients with rheumatoid arthritis. Arthritis Rheum 54:3104–3112. [PubMed][CrossRef]
155. Harre U, Georgess D, Bang H, Bozec A, Axmann R, Ossipova E, Jakobsson P-J, Baum W, Nimmerjahn F, Szarka E, Sarmay G, Krumbholz G, Neumann E, Toes R, Scherer HU, Catrina AI, Klareskog L, Jurdic P, Schett G. 2012. Induction of osteoclastogenesis and bone loss by human autoantibodies against citrullinated vimentin. J Clin Invest 122:1791–1802. [PubMed][CrossRef]
156. Seki N, Sudo Y, Yoshioka T, Sugihara S, Fujitsu T, Sakuma S, Ogawa T, Hamaoka T, Senoh H, Fujiwara H. 1988. Type II collagen-induced murine arthritis. I. Induction and perpetuation of arthritis require synergy between humoral and cell-mediated immunity. J Immunol 140:1477–1484. [PubMed]
157. Brackertz D, Mitchell GF, Mackay IR. 1977. Antigen-induced arthritis in mice. I. Induction of arthritis in various strains of mice. Arthritis Rheum 20:841–850. [PubMed][CrossRef]
158. Korganow AS, Ji H, Mangialaio S, Duchatelle V, Pelanda R, Martin T, Degott C, Kikutani H, Rajewsky K, Pasquali JL, Benoist C, Mathis D. 1999. From systemic T cell self-reactivity to organ-specific autoimmune disease via immunoglobulins. Immunity 10:451–461. [PubMed][CrossRef]
159. Khachigian LM. 2006. Collagen antibody-induced arthritis. Nat Protoc 1:2512–2516. [PubMed][CrossRef]
160. Keffer J, Probert L, Cazlaris H, Georgopoulos S, Kaslaris E, Kioussis D, Kollias G. 1991. Transgenic mice expressing human tumour necrosis factor: a predictive genetic model of arthritis. EMBO J 10:4025–4031. [PubMed]
161. Li P, Schwarz E. 2003. The TNF-α transgenic mouse model of inflammatory arthritis. Springer Semin Immunopathol 25:19–33. [PubMed][CrossRef]
162. Mukai T, Gallant R, Ishida S, Kittaka M, Yoshitaka T, Fox DA, Morita Y, Nishida K, Rottapel R, Ueki Y. 2015. Loss of SH3 domain-binding protein 2 function suppresses bone destruction in tumor necrosis factor-driven and collagen-induced arthritis in mice. Arthritis Rheumatol 67:656–667. [PubMed][CrossRef]
163. Aya K, Alhawagri M, Hagen-Stapleton A, Kitaura H, Kanagawa O, Novack DV. 2005. NF-κB-inducing kinase controls lymphocyte and osteoclast activities in inflammatory arthritis. J Clin Invest 115:1848–1854. [PubMed][CrossRef]
164. Cremasco V, Benasciutti E, Cella M, Kisseleva M, Croke M, Faccio R. 2010. Phospholipase C gamma 2 is critical for development of a murine model of inflammatory arthritis by affecting actin dynamics in dendritic cells. PLoS One 5:e8909. doi:10.1371/journal.pone.0008909. [CrossRef]
165. Masters SL, Simon A, Aksentijevich I, Kastner DL. 2009. Horror autoinflammaticus: the molecular pathophysiology of autoinflammatory disease. Annu Rev Immunol 27:621–668. [PubMed][CrossRef]
166. Hill S, Namde M, Dwyer A, Poznanski A, Canna S, Goldbach-Mansky R. 2007. Arthropathy of neonatal onset multisystem inflammatory disease (NOMID/CINCA). Pediatr Radiol 37:145–152. [PubMed][CrossRef]
167. Schoindre Y, Feydy A, Giraudet-Lequintrec JS, Kahan A, Allanore Y. 2009. TNF receptor-associated periodic syndrome (TRAPS): a new cause of joint destruction? Joint Bone Spine 76:567–569. [PubMed][CrossRef]
168. Koca SS, Etem EO, Isik B, Yuce H, Ozgen M, Dag MS, Isik A. 2010. Prevalence and significance of MEFV gene mutations in a cohort of patients with rheumatoid arthritis. Joint Bone Spine 77:32–35. [PubMed][CrossRef]
169. Lang BA, Schneider R, Reilly BJ, Silverman ED, Laxer RM. 1995. Radiologic features of systemic onset juvenile rheumatoid arthritis. J Rheumatol 22:168–173. [PubMed]
170. Rosé CD, Pans S, Casteels I, Anton J, Bader-Meunier B, Brissaud P, Cimaz R, Espada G, Fernandez-Martin J, Hachulla E, Harjacek M, Khubchandani R, Mackensen F, Merino R, Naranjo A, Oliveira-Knupp S, Pajot C, Russo R, Thomée C, Vastert S, Wulffraat N, Arostegui JI, Foley KP, Bertin J, Wouters CH. 2015. Blau syndrome: cross-sectional data from a multicentre study of clinical, radiological and functional outcomes. Rheumatology (Oxford) 54:1008–1016. [PubMed][CrossRef]
171. Chen B, Wu W, Sun W, Zhang Q, Yan F, Xiao Y. 2014. RANKL expression in periodontal disease: where does RANKL come from? BioMed Res Int 731039: doi:10.1155/2014/731039. [PubMed][CrossRef]
172. Zhang P, Liu J, Xu Q, Harber G, Feng X, Michalek SM, Katz J. 2011. TLR2-dependent modulation of osteoclastogenesis by Porphyromonas gingivalis through differential induction of NFATc1 and NF-κB. J Biol Chem 286:24159–24169. [PubMed][CrossRef]
173. Assuma R, Oates T, Cochran D, Amar S, Graves DT. 1998. IL-1 and TNF antagonists inhibit the inflammatory response and bone loss in experimental periodontitis. J Immunol 160:403–409. [PubMed]
174. Graves DT, Oskoui M, Voleinikova S, Naguib G, Cai S, Desta T, Kakouras A, Jiang Y. 2001. Tumor necrosis factor modulates fibroblast apoptosis, PMN recruitment, and osteoclast formation in response to P. gingivalis infection. J Dent Res 80:1875–1879. [PubMed][CrossRef]
175. Weilbaecher KN, Guise TA, McCauley LK. 2011. Cancer to bone: a fatal attraction. Nat Rev Cancer 11:411–425. [PubMed][CrossRef]
176. Hirbe AC, Uluçkan O, Morgan EA, Eagleton MC, Prior JL, Piwnica-Worms D, Trinkaus K, Apicelli A, Weilbaecher K. 2007. Granulocyte colony-stimulating factor enhances bone tumor growth in mice in an osteoclast-dependent manner. Blood 109:3424–3431. [PubMed][CrossRef]
177. Yang C, Davis JL, Zeng R, Vora P, Su X, Collins LI, Vangveravong S, Mach RH, Piwnica-Worms D, Weilbaecher KN, Faccio R, Novack DV. 2013. Antagonism of inhibitor of apoptosis proteins increases bone metastasis via unexpected osteoclast activation. Cancer Discov 3:212–223. [PubMed][CrossRef]
178. Morony S, Capparelli C, Sarosi I, Lacey DL, Dunstan CR, Kostenuik PJ. 2001. Osteoprotegerin inhibits osteolysis and decreases skeletal tumor burden in syngeneic and nude mouse models of experimental bone metastasis. Cancer Res 61:4432–4436. [PubMed]
179. Canon JR, Roudier M, Bryant R, Morony S, Stolina M, Kostenuik PJ, Dougall WC. 2008. Inhibition of RANKL blocks skeletal tumor progression and improves survival in a mouse model of breast cancer bone metastasis. Clin Exp Metastasis 25:119–129. [PubMed][CrossRef]
180. Gampenrieder SP, Rinnerthaler G, Greil R. 2014. Bone-targeted therapy in metastatic breast cancer—all well-established knowledge? Breast Care (Basel) 9:323–330. [PubMed][CrossRef]
181. Otero K, Shinohara M, Zhao H, Cella M, Gilfillan S, Colucci A, Faccio R, Ross FP, Teitelbaum SL, Takayanagi H, Colonna M. 2012. TREM2 and β-catenin regulate bone homeostasis by controlling the rate of osteoclastogenesis. J Immunol 188:2612–2621. [PubMed][CrossRef]
182. Oba Y, Lee JW, Ehrlich LA, Chung HY, Jelinek DF, Callander NS, Horuk R, Choi SJ, Roodman GD. 2005. MIP-1α utilizes both CCR1 and CCR5 to induce osteoclast formation and increase adhesion of myeloma cells to marrow stromal cells. Exp Hematol 33:272–278. [PubMed][CrossRef]
183. Han JH, Choi SJ, Kurihara N, Koide M, Oba Y, Roodman GD. 2001. Macrophage inflammatory protein-1α is an osteoclastogenic factor in myeloma that is independent of receptor activator of nuclear factor κB ligand. Blood 97:3349–3353. [PubMed][CrossRef]
184. Tawara K, Oxford JT, Jorcyk CL. 2011. Clinical significance of interleukin (IL)-6 in cancer metastasis to bone: potential of anti-IL-6 therapies. Cancer Manag Res 3:177–189. [PubMed]
185. Hurchla MA, Garcia-Gomez A, Hornick MC, Ocio EM, Li A, Blanco JF, Collins L, Kirk CJ, Piwnica-Worms D, Vij R, Tomasson MH, Pandiella A, San Miguel JF, Garayoa M, Weilbaecher KN. 2013. The epoxyketone-based proteasome inhibitors carfilzomib and orally bioavailable oprozomib have anti-resorptive and bone-anabolic activity in addition to anti-myeloma effects. Leukemia 27:430–440. [PubMed][CrossRef]
186. von Metzler I, Krebbel H, Hecht M, Manz RA, Fleissner C, Mieth M, Kaiser M, Jakob C, Sterz J, Kleeberg L, Heider U, Sezer O. 2007. Bortezomib inhibits human osteoclastogenesis. Leukemia 21:2025–2034. [PubMed][CrossRef]
187. Boissy P, Andersen TL, Lund T, Kupisiewicz K, Plesner T, Delaissé JM. 2008. Pulse treatment with the proteasome inhibitor bortezomib inhibits osteoclast resorptive activity in clinically relevant conditions. Leuk Res 32:1661–1668. [PubMed][CrossRef]
188. Keats JJ, Fonseca R, Chesi M, Schop R, Baker A, Chng WJ, Van Wier S, Tiedemann R, Shi CX, Sebag M, Braggio E, Henry T, Zhu YX, Fogle H, Price-Troska T, Ahmann G, Mancini C, Brents LA, Kumar S, Greipp P, Dispenzieri A, Bryant B, Mulligan G, Bruhn L, Barrett M, Valdez R, Trent J, Stewart AK, Carpten J, Bergsagel PL. 2007. Promiscuous mutations activate the noncanonical NF-κB pathway in multiple myeloma. Cancer Cell 12:131–144. [PubMed][CrossRef]
189. Annunziata CM, Davis RE, Demchenko Y, Bellamy W, Gabrea A, Zhan F, Lenz G, Hanamura I, Wright G, Xiao W, Dave S, Hurt EM, Tan B, Zhao H, Stephens O, Santra M, Williams DR, Dang L, Barlogie B, Shaughnessy JD Jr, Kuehl WM, Staudt LM. 2007. Frequent engagement of the classical and alternative NF-κB pathways by diverse genetic abnormalities in multiple myeloma. Cancer Cell 12:115–130. [PubMed][CrossRef]
190. Vaira S, Johnson T, Hirbe AC, Alhawagri M, Anwisye I, Sammut B, O’Neal J, Zou W, Weilbaecher KN, Faccio R, Novack DV. 2008. RelB is the NF-κB subunit downstream of NIK responsible for osteoclast differentiation. Proc Natl Acad Sci USA 105:3897–3902. [PubMed][CrossRef]
191. Novack DV, Yin L, Hagen-Stapleton A, Schreiber RD, Goeddel DV, Ross FP, Teitelbaum SL. 2003. The IκB function of NF-κB2 p100 controls stimulated osteoclastogenesis. J Exp Med 198:771–781. [PubMed][CrossRef]
192. Yang C, McCoy K, Davis JL, Schmidt-Supprian M, Sasaki Y, Faccio R, Novack DV. 2010. NIK stabilization in osteoclasts results in osteoporosis and enhanced inflammatory osteolysis. PLoS One 5:e15383. doi:10.1371/journal.pone.0015383. [PubMed][CrossRef]
193. Demchenko YN, Brents LA, Li Z, Bergsagel LP, McGee LR, Kuehl MW. 2014. Novel inhibitors are cytotoxic for myeloma cells with NFkB inducing kinase-dependent activation of NFkB. Oncotarget 5:4554–4566. [PubMed][CrossRef]
194. Kameda T, Mano H, Yuasa T, Mori Y, Miyazawa K, Shiokawa M, Nakamaru Y, Hiroi E, Hiura K, Kameda A, Yang NN, Hakeda Y, Kumegawa M. 1997. Estrogen inhibits bone resorption by directly inducing apoptosis of the bone-resorbing osteoclasts. J Exp Med 186:489–495. [PubMed][CrossRef]
195. Hughes DE, Dai A, Tiffee JC, Li HH, Mundy GR, Boyce BF. 1996. Estrogen promotes apoptosis of murine osteoclasts mediated by TGF-beta. Nat Med 2:1132–1136. [PubMed][CrossRef]
196. Nakamura T, Imai Y, Matsumoto T, Sato S, Takeuchi K, Igarashi K, Harada Y, Azuma Y, Krust A, Yamamoto Y, Nishina H, Takeda S, Takayanagi H, Metzger D, Kanno J, Takaoka K, Martin TJ, Chambon P, Kato S. 2007. Estrogen prevents bone loss via estrogen receptor α and induction of Fas ligand in osteoclasts. Cell 130:811–823. [PubMed][CrossRef]
197. Shevde NK, Bendixen AC, Dienger KM, Pike JW. 2000. Estrogens suppress RANK ligand-induced osteoclast differentiation via a stromal cell independent mechanism involving c-Jun repression. Proc Natl Acad Sci USA 97:7829–7834. [PubMed][CrossRef]
198. Shevde N, Pike J. 1996. Estrogen modulates the recruitment of myelopoietic cell progenitors in rat through a stromal cell-independent mechanism involving apoptosis. Blood 87:2683–2692. [PubMed]
199. D’Amelio P, Grimaldi A, Pescarmona GP, Tamone C, Roato I, Isaia G. 2004. Spontaneous osteoclast formation from peripheral blood mononuclear cells in postmenopausal osteoporosis. FASEB J 19:410–412. [CrossRef]
200. Slyfield CR, Tkachenko EV, Wilson DL, Hernandez CJ. 2012. Three-dimensional dynamic bone histomorphometry. J Bone Miner Res 27:486–495. [PubMed][CrossRef]
201. Martin-Millan M, Almeida M, Ambrogini E, Han L, Zhao H, Weinstein RS, Jilka RL, O’Brien CA, Manolagas SC. 2010. The estrogen receptor-α in osteoclasts mediates the protective effects of estrogens on cancellous but not cortical bone. Mol Endocrinol 24:323–334. [PubMed][CrossRef]
202. Almeida M, Iyer S, Martin-Millan M, Bartell SM, Han L, Ambrogini E, Onal M, Xiong J, Weinstein RS, Jilka RL, O’Brien CA, Manolagas SC. 2013. Estrogen receptor-α signaling in osteoblast progenitors stimulates cortical bone accrual. J Clin Invest 123:394–404. [PubMed][CrossRef]
203. Khosla S. 2010. Pathogenesis of osteoporosis. Transl Endocrinol Metab 1:55–86. [PubMed][CrossRef]
204. Roggia C, Gao Y, Cenci S, Weitzmann MN, Toraldo G, Isaia G, Pacifici R. 2001. 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. [PubMed][CrossRef]
205. Charatcharoenwitthaya N, Khosla S, Atkinson EJ, McCready LK, Riggs BL. 2007. Effect of blockade of TNF-α and interleukin-1 action on bone resorption in early postmenopausal women. J Bone Miner Res 22:724–729. [PubMed][CrossRef]
206. Johnson RA, Boyce BF, Mundy GR, Roodman GD. 1989. Tumors producing human tumor necrosis factor induce hypercalcemia and osteoclastic bone resorption in nude mice. Endocrinology 124:1424–1427. [PubMed][CrossRef]
207. Pfeilschifter J, Chenu C, Bird A, Mundy GR, Roodman DG. 1989. Interleukin-1 and tumor necrosis factor stimulate the formation of human osteoclastlike cells in vitro. J Bone Miner Res 4:113–118. [PubMed][CrossRef]
208. Wei S, Kitaura H, Zhou P, Ross FP, Teitelbaum SL. 2005. IL-1 mediates TNF-induced osteoclastogenesis. J Clin Invest 115:282–290. [PubMed][CrossRef]
209. Kaplan DL, Eielson CM, Horowitz MC, Insogna KL, Weir EC. 1996. Tumor necrosis factor-α induces transcription of the colony-stimulating factor-1 gene in murine osteoblasts. J Cell Physiol 168:199–208. [PubMed][CrossRef]
210. Azuma Y, Kaji K, Katogi R, Takeshita S, Kudo A. 2000. Tumor necrosis factor-α induces differentiation of and bone resorption by osteoclasts. J Biol Chem 275:4858–4864. [PubMed][CrossRef]
211. Kobayashi K, Takahashi N, Jimi E, Udagawa N, Takami M, Kotake S, Nakagawa N, Kinosaki M, Yamaguchi K, Shima N, Yasuda H, Morinaga T, Higashio K, Martin TJ, Suda T. 2000. Tumor necrosis factor α stimulates osteoclast differentiation by a mechanism independent of the ODF/RANKL-RANK interaction. J Exp Med 191:275–286. [PubMed][CrossRef]
212. Kanazawa K, Kudo A. 2005. TRAF2 is essential for TNF-α-induced osteoclastogenesis. J Bone Miner Res 20:840–847. [PubMed][CrossRef]
213. Kudo O, Fujikawa Y, Itonaga I, Sabokbar A, Torisu T, Athanasou NA. 2002. Proinflammatory cytokine (TNFα/IL-1α) induction of human osteoclast formation. J Pathol 198:220–227. [PubMed][CrossRef]
214. O’Gradaigh D, Ireland D, Bord S, Compston JE. 2004. Joint erosion in rheumatoid arthritis: interactions between tumour necrosis factor α, interleukin 1, and receptor activator of nuclear factor κB ligand (RANKL) regulate osteoclasts. Ann Rheum Dis 63:354–359. [CrossRef]
215. Yao Z, Xing L, Boyce BF. 2009. NF-κB p100 limits TNF-induced bone resorption in mice by a TRAF3-dependent mechanism. J Clin Invest 119:3024–3034. [PubMed][CrossRef]
216. 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 209:319–334. [PubMed][CrossRef]
217. Nakamura I, Jimi E. 2006. Regulation of osteoclast differentiation and function by interleukin-1. Vitam Horm 74:357–370. [PubMed][CrossRef]
218. Ma T, Miyanishi K, Suen A, Epstein NJ, Tomita T, Smith RL, Goodman SB. 2004. Human interleukin-1-induced murine osteoclastogenesis is dependent on RANKL, but independent of TNF-α. Cytokine 26:138–144. [PubMed][CrossRef]
219. Jules J, Zhang P, Ashley JW, Wei S, Shi Z, Liu J, Michalek SM, Feng X. 2012. Molecular basis of requirement of receptor activator of nuclear factor κB signaling for interleukin 1-mediated osteoclastogenesis. J Biol Chem 287:15728–15738. [PubMed][CrossRef]
220. Kim JH, Jin HM, Kim K, Song I, Youn BU, Matsuo K, Kim N. 2009. The mechanism of osteoclast differentiation induced by IL-1. J Immunol 183:1862–1870. [PubMed][CrossRef]
221. Nakamura I, Kadono Y, Takayanagi H, Jimi E, Miyazaki T, Oda H, Nakamura K, Tanaka S, Rodan GA, Duong LT. 2002. IL-1 regulates cytoskeletal organization in osteoclasts via TNF receptor-associated factor 6/c-Src complex. J Immunol 168:5103–5109. [PubMed][CrossRef]
222. Jimi E, Nakamura I, Ikebe T, Akiyama S, Takahashi N, Suda T. 1998. Activation of NF-κB is involved in the survival of osteoclasts promoted by interleukin-1. J Biol Chem 273:8799–8805. [PubMed][CrossRef]
223. Jimi E, Nakamura I, Duong LT, Ikebe T, Takahashi N, Rodan GA, Suda T. 1999. Interleukin 1 induces multinucleation and bone-resorbing activity of osteoclasts in the absence of osteoblasts/stromal cells. Exp Cell Res 247:84–93. [PubMed][CrossRef]
224. Fox SW, Haque SJ, Lovibond AC, Chambers TJ. 2003. The possible role of TGF-β-induced suppressors of cytokine signaling expression in osteoclast/macrophage lineage commitment in vitro. J Immunol 170:3679–3687. [PubMed][CrossRef]
225. Yan T, Riggs BL, Boyle WJ, Khosla S. 2001. Regulation of osteoclastogenesis and RANK expression by TGF-β1. J Cell Biochem 83:320–325. [PubMed][CrossRef]
226. Fox SW, Lovibond AC. 2005. Current insights into the role of transforming growth factor-β in bone resorption. Mol Cell Endocrinol 243:19–26. [PubMed][CrossRef]
227. Yasui T, Kadono Y, Nakamura M, Oshima Y, Matsumoto T, Masuda H, Hirose J, Omata Y, Yasuda H, Imamura T, Nakamura K, Tanaka S. 2011. Regulation of RANKL-induced osteoclastogenesis by TGF-β through molecular interaction between Smad3 and Traf6. J Bone Miner Res 26:1447–1456. [PubMed][CrossRef]
228. Omata Y, Yasui T, Hirose J, Izawa N, Imai Y, Matsumoto T, Masuda H, Tokuyama N, Nakamura S, Tsutsumi S, Yasuda H, Okamoto K, Takayanagi H, Hikita A, Imamura T, Matsuo K, Saito T, Kadono Y, Aburatani H, Tanaka S. 2014. Genome-wide comprehensive analysis reveals critical cooperation between Smad and c-Fos in RANKL-induced osteoclastogenesis. J Bone Miner Res 30:869–877. [PubMed][CrossRef]
229. Asai K, Funaba M, Murakami M. 2014. Enhancement of RANKL-induced MITF-E expression and osteoclastogenesis by TGF-β. Cell Biochem Funct 32:401–409. [PubMed]
230. Mansky KC, Sankar U, Han J, Ostrowski MC. 2002. Microphthalmia transcription factor is a target of the p38 MAPK pathway in response to receptor activator of NF-κB ligand signaling. J Biol Chem 277:11077–11083. [PubMed][CrossRef]
231. Fuller K, Kirstein B, Chambers TJ. 2006. Murine osteoclast formation and function: differential regulation by humoral agents. Endocrinology 147:1979–1985. [PubMed][CrossRef]
232. Mundy GR. 1991. The effects of TGF-beta on bone. Ciba Found Symp 157:137–143, discussion 143–151. [PubMed]
233. Dieudonne SC, Foo P, van Zoelen EJ, Burger EH. 1991. Inhibiting and stimulating effects of TGF-β 1 on osteoclastic bone resorption in fetal mouse bone organ cultures. J Bone Miner Res 6:479–487. [PubMed][CrossRef]
234. Edwards JR, Nyman JS, Lwin ST, Moore MM, Esparza J, O’Quinn EC, Hart AJ, Biswas S, Patil CA, Lonning S, Mahadevan-Jansen A, Mundy GR. 2010. Inhibition of TGF-β signaling by 1D11 antibody treatment increases bone mass and quality in vivo. J Bone Miner Res 25:2419–2426. [PubMed][CrossRef]
235. Mohammad KS, Chen CG, Balooch G, Stebbins E, McKenna CR, Davis H, Niewolna M, Peng XH, Nguyen DHN, Ionova-Martin SS, Bracey JW, Hogue WR, Wong DH, Ritchie RO, Suva LJ, Derynck R, Guise TA, Alliston T. 2009. Pharmacologic inhibition of the TGF-β type I receptor kinase has anabolic and anti-catabolic effects on bone. PLoS One 4:e5275. doi:10.1371/journal.pone.0005275. [CrossRef]
236. Yin JJ, Selander K, Chirgwin JM, Dallas M, Grubbs BG, Wieser R, Massagué J, Mundy GR, Guise TA. 1999. TGF-β signaling blockade inhibits PTHrP secretion by breast cancer cells and bone metastases development. J Clin Invest 103:197–206. [PubMed][CrossRef]
237. Massagué J. 2012. TGFβ signalling in context. Nat Rev Mol Cell Biol 13:616–630. [PubMed][CrossRef]
238. Bragado P, Estrada Y, Parikh F, Krause S, Capobianco C, Farina HG, Schewe DM, Aguirre-Ghiso JA. 2013. TGFβ2 dictates disseminated tumour cell fate in target organs through TGFβ-RIII and p38α/β signalling. Nat Cell Biol 15:1351–1361. [PubMed][CrossRef]
239. Liu S, Song W, Boulanger JH, Tang W, Sabbagh Y, Kelley B, Gotschall R, Ryan S, Phillips L, Malley K, Cao X, Xia TH, Zhen G, Cao X, Ling H, Dechow PC, Bellido TM, Ledbetter SR, Schiavi SC. 2014. Role of TGF-β in a mouse model of high turnover renal osteodystrophy. J Bone Miner Res 29:1141–1157. [PubMed][CrossRef]
240. Nistala H, Lee-Arteaga S, Smaldone S, Siciliano G, Ramirez F. 2010. Extracellular microfibrils control osteoblast-supported osteoclastogenesis by restricting TGFβ stimulation of RANKL production. J Biol Chem 285:34126–34133. [PubMed][CrossRef]
241. Hayata T, Yoichi, Ezura, Asashima M, Nishinakamura R, Noda M. 2015. Dullard/Ctdnep1 regulates endochondral ossification via suppression of TGF-β signaling. J Bone Miner Res 30:318–329. [PubMed][CrossRef]
242. Craft CS, Broekelmann TJ, Zou W, Chappel JC, Teitelbaum SL, Mecham RP. 2012. Oophorectomy-induced bone loss is attenuated in MAGP1-deficient mice. J Cell Biochem 113:93–99. [PubMed][CrossRef]
243. Rhodes SD, Wu X, He Y, Chen S, Yang H, Staser KW, Wang J, Zhang P, Jiang C, Yokota H, Dong R, Peng X, Yang X, Murthy S, Azhar M, Mohammad KS, Xu M, Guise TA, Yang FC. 2013. Hyperactive transforming growth factor-β1 signaling potentiates skeletal defects in a neurofibromatosis type 1 mouse model. J Bone Miner Res 28:2476–2489. [PubMed][CrossRef]
244. Takayanagi H, Ogasawara K, Hida S, Chiba T, Murata S, Sato K, Takaoka A, Yokochi T, Oda H, Tanaka K, Nakamura K, Taniguchi T. 2000. T-cell-mediated regulation of osteoclastogenesis by signalling cross-talk between RANKL and IFN-γ. Nature 408:600–605. [PubMed][CrossRef]
245. Ji JD, Park-Min KH, Shen Z, Fajardo RJ, Goldring SR, McHugh KP, Ivashkiv LB. 2009. Inhibition of RANK expression and osteoclastogenesis by TLRs and IFN-γ in human osteoclast precursors. J Immunol 183:7223–7233. [PubMed][CrossRef]
246. Huang W, O’Keefe R, Schwarz E. 2003. Exposure to receptor-activator of NFκB ligand renders pre-osteoclasts resistant to IFN-γ by inducing terminal differentiation. Arthritis Res Ther 5:R49–R59. [PubMed][CrossRef]
247. Vermeire K, Heremans H, Vandeputte M, Huang S, Billiau A, Matthys P. 1997. Accelerated collagen-induced arthritis in IFN-γ receptor-deficient mice. J Immunol 158:5507–5513. [PubMed]
248. Xu Z, Hurchla MA, Deng H, Uluçkan O, Bu F, Berdy A, Eagleton MC, Heller EA, Floyd DH, Dirksen WP, Shu S, Tanaka Y, Fernandez SA, Rosol TJ, Weilbaecher KN. 2009. Interferon-γ targets cancer cells and osteoclasts to prevent tumor-associated bone loss and bone metastases. J Biol Chem 284:4658–4666. [PubMed][CrossRef]
249. Key LL Jr, Rodriguiz RM, Willi SM, Wright NM, Hatcher HC, Eyre DR, Cure JK, Griffin PP, Ries WL. 1995. Long-term treatment of osteopetrosis with recombinant human interferon gamma. N Engl J Med 332:1594–1599. [PubMed][CrossRef]
250. Madyastha PR, Yang S, Ries WL, Key LL Jr. 2000. IFN-γ enhances osteoclast generation in cultures of peripheral blood from osteopetrotic patients and normalizes superoxide production. J Interferon Cytokine Res 20:645–652. [PubMed][CrossRef]
251. Cenci S, Toraldo G, Weitzmann MN, Roggia C, Gao Y, Qian WP, Sierra O, Pacifici R. 2003. Estrogen deficiency induces bone loss by increasing T cell proliferation and lifespan through IFN-γ-induced class II transactivator. Proc Natl Acad Sci USA 100:10405–10410. [PubMed][CrossRef]
252. Gao Y, Grassi F, Ryan MR, Terauchi M, Page K, Yang X, Weitzmann MN, Pacifici R. 2007. IFN-γ stimulates osteoclast formation and bone loss in vivo via antigen-driven T cell activation. J Clin Invest 117:122–132. [PubMed][CrossRef]
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/content/journal/microbiolspec/10.1128/microbiolspec.MCHD-0011-2015
2016-06-10
2021-04-11

Abstract:

The differentiation of osteoclasts (OCs) from early myeloid progenitors is a tightly regulated process that is modulated by a variety of mediators present in the bone microenvironment. Once generated, the function of mature OCs depends on cytoskeletal features controlled by an αβ-containing complex at the bone-apposed membrane and the secretion of protons and acid-protease cathepsin K. OCs also have important interactions with other cells in the bone microenvironment, including osteoblasts and immune cells. Dysregulation of OC differentiation and/or function can cause bone pathology. In fact, many components of OC differentiation and activation have been targeted therapeutically with great success. However, questions remain about the identity and plasticity of OC precursors and the interplay between essential networks that control OC fate. In this review, we summarize the key principles of OC biology and highlight recently uncovered mechanisms regulating OC development and function in homeostatic and disease states.

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Osteoclasts—Key Players in Skeletal Health and Disease
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Citation: Novack D, Mbalaviele G. 2016. Osteoclasts—key players in skeletal health and disease. microbiolspec 4(3): doi:10.1128/microbiolspec.MCHD-0011-2015
/content/microbiolspec/10.1128/microbiolspec.MCHD-0011-2015.fig1
FIGURE 1
A model of OC differentiation. OCs differentiate from HSCs. The hematopoietic niche comprises endothelial cells and perivascular stromal cells, which exhibit mesenchymal stem cell (MSC) features. It is still unclear whether OC precursors directly differentiate into OCs or enter the bloodstream before reentering the bone microenvironment to form OCs. In any scenario, higher levels of chemoattractants toward bone surfaces, including bone ECM proteins, lipid mediators (e.g., sphingosine-1-phosphate), and ECM degradation products, create gradients that attract OC precursors to the hard tissue, where they fuse and complete the differentiation process. Conversely, higher levels of perivascular chemorepellents (not drawn for simplicity) may also contribute to the migration of OC precursors toward the endosteum.
microbiolspec/4/3/MCHD-0011-2015-fig1_thmb.gif
microbiolspec/4/3/MCHD-0011-2015-fig1.gif
Image of FIGURE 1

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FIGURE 1

A model of OC differentiation. OCs differentiate from HSCs. The hematopoietic niche comprises endothelial cells and perivascular stromal cells, which exhibit mesenchymal stem cell (MSC) features. It is still unclear whether OC precursors directly differentiate into OCs or enter the bloodstream before reentering the bone microenvironment to form OCs. In any scenario, higher levels of chemoattractants toward bone surfaces, including bone ECM proteins, lipid mediators (e.g., sphingosine-1-phosphate), and ECM degradation products, create gradients that attract OC precursors to the hard tissue, where they fuse and complete the differentiation process. Conversely, higher levels of perivascular chemorepellents (not drawn for simplicity) may also contribute to the migration of OC precursors toward the endosteum.

Source: microbiolspec June 2016 vol. 4 no. 3 doi:10.1128/microbiolspec.MCHD-0011-2015
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/content/microbiolspec/10.1128/microbiolspec.MCHD-0011-2015.fig2
FIGURE 2
Key molecules involved in OC function. Loss of function of any of the depicted molecules causes osteopetrosis due to defective OC activity. OCs adhere to bone matrix proteins via integrin αβ and are polarized such that the plasma membrane-facing bone is convoluted (ruffled) and contains the proton pump (v-ATPase) and Cl channel 7 (ClC7), whereas the basolateral membrane bears the HCO /Cl antiporter. Cytoplasmic carbonic anhydrase type II (CAII) generates the protons to be secreted into the resorption lacuna beneath the cell. This lacuna becomes isolated from the rest of the extracellular space by the tight adhesion of αβ to the bone surface at the sealing zone. The cytoplasmic domain of β recruits signaling proteins, which induce the association of actin with interacting partners (including talin, vinculin, kindlin, myosin IIA, and paxillin) and formation of an actin ring that defines the periphery of the ruffled membrane. Concerted action of ClC7 and v-ATPase produces a high concentration of HCl that acidifies the resorption lacuna, leading to the dissolution of the inorganic components of the bone matrix. Acidified cytoplasmic vesicles containing lysosomal enzymes such as cathepsin K (Cat K) are also transported toward the bone-apposed plasma membrane and, ultimately, the sealed resorption lacuna, where they digest the exposed matrix proteins.
microbiolspec/4/3/MCHD-0011-2015-fig2_thmb.gif
microbiolspec/4/3/MCHD-0011-2015-fig2.gif
Image of FIGURE 2

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FIGURE 2

Key molecules involved in OC function. Loss of function of any of the depicted molecules causes osteopetrosis due to defective OC activity. OCs adhere to bone matrix proteins via integrin αβ and are polarized such that the plasma membrane-facing bone is convoluted (ruffled) and contains the proton pump (v-ATPase) and Cl channel 7 (ClC7), whereas the basolateral membrane bears the HCO /Cl antiporter. Cytoplasmic carbonic anhydrase type II (CAII) generates the protons to be secreted into the resorption lacuna beneath the cell. This lacuna becomes isolated from the rest of the extracellular space by the tight adhesion of αβ to the bone surface at the sealing zone. The cytoplasmic domain of β recruits signaling proteins, which induce the association of actin with interacting partners (including talin, vinculin, kindlin, myosin IIA, and paxillin) and formation of an actin ring that defines the periphery of the ruffled membrane. Concerted action of ClC7 and v-ATPase produces a high concentration of HCl that acidifies the resorption lacuna, leading to the dissolution of the inorganic components of the bone matrix. Acidified cytoplasmic vesicles containing lysosomal enzymes such as cathepsin K (Cat K) are also transported toward the bone-apposed plasma membrane and, ultimately, the sealed resorption lacuna, where they digest the exposed matrix proteins.

Source: microbiolspec June 2016 vol. 4 no. 3 doi:10.1128/microbiolspec.MCHD-0011-2015
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