Chapter 13 : Osteoclasts—Key Players in Skeletal Health and Disease

MyBook is a cheap paperback edition of the original book and will be sold at uniform, low price.

Preview this chapter:
Zoom in

Osteoclasts—Key Players in Skeletal Health and Disease, Page 1 of 2

| /docserver/preview/fulltext/10.1128/9781555819194/9781555819187_Chap13-1.gif /docserver/preview/fulltext/10.1128/9781555819194/9781555819187_Chap13-2.gif


Although bone is one of the hardest tissues in the body, necessary for its structural and protective roles, this organ is not static. Bone matrix must be renewed over time in order to maintain its mechanical properties, and myeloid lineage cells called osteoclasts (OCs) are the specialized cells that perform this critical function. Since bone is the major storage site for calcium, OCs play an important role in the regulation of this signaling ion by releasing it from bone. In this process, OCs respond indirectly to calcium-regulating hormones such as parathyroid hormone and 1,25(OH) vitamin D. Growth factors such as insulin-like growth factor-1 (IGF-1) and transforming growth factor β (TGF-β) are also incorporated into bone matrix and released by OCs, affecting the coupling of bone formation to bone resorption and potentially targeting other cells in the microenvironment, such as metastatic tumors. Lastly, OCs retain features of other myeloid cells, such as antigen presentation and cytokine production, which afford them the potential to affect immune responses. Thus, the OC plays many roles in health and disease.

Citation: Novack D, Mbalaviele G. 2017. Osteoclasts—Key Players in Skeletal Health and Disease, p 235-255. In Gordon S (ed), Myeloid Cells in Health and Disease. ASM Press, Washington, DC. doi: 10.1128/microbiolspec.MCHD-0011-2015
Highlighted Text: Show | Hide
Loading full text...

Full text loading...


Image of Figure 1
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.

Citation: Novack D, Mbalaviele G. 2017. Osteoclasts—Key Players in Skeletal Health and Disease, p 235-255. In Gordon S (ed), Myeloid Cells in Health and Disease. ASM Press, Washington, DC. doi: 10.1128/microbiolspec.MCHD-0011-2015
Permissions and Reprints Request Permissions
Download as Powerpoint
Image of Figure 2
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.

Citation: Novack D, Mbalaviele G. 2017. Osteoclasts—Key Players in Skeletal Health and Disease, p 235-255. In Gordon S (ed), Myeloid Cells in Health and Disease. ASM Press, Washington, DC. doi: 10.1128/microbiolspec.MCHD-0011-2015
Permissions and Reprints Request Permissions
Download as Powerpoint


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,, Aksentij