1. Teitelbaum SL. Bone resorption by osteoclasts. Science. 289:1504–1508. 2000.

2. Suda T, Takahashi N, Udagawa N, Jimi E, Gillespie MT, Martin TJ. Modulation of osteoclast differentiation and function by the new members of the tumor necrosis factor receptor and ligand families. Endocr Rev. 20:345–357. 1999.

3. Aubin JE. Regulation of osteoblast formation and function. Rev Endocr Metab Disord. 2:81–94. 2001.

4. Chambers TJ. Regulation of the differentiation and function of osteoclasts. J Pathol. 192:4–13. 2000.

5. Vignery A. Osteoclasts and giant cells: macrophage-macrophage fusion mechanism. Int J Exp Pathol. 81:291–304. 2000.

6. Udagawa N, Takahashi N, Akatsu T, Tanaka H, Sasaki T, Nishihara T, Koga T, Martin TJ, Suda T. Origin of osteoclasts: mature monocytes and macrophages are capable of differentiating into osteoclasts under a suitable microenvironment prepared by bone marrowderived stromal cells. Proc Natl Acad Sci U S A. 87:7260–7264. 1990.

7. McHugh KP, Hodivala-Dilke K, Zheng MH, Namba N, Lam J, Novack D, Feng X, Ross FP, Hynes RO, Teitelbaum SL. Mice lacking beta3 integrins are osteosclerotic because of dysfunctional osteoclasts. J Clin Invest. 105:433–440. 2000.

8. Soriano P, Montgomery C, Geske R, Bradley A. Targeted disruption of the c-src proto-oncogene leads to osteopetrosis in mice. Cell. 64:693–702. 1991.

9. Boyce BF, Yoneda T, Lowe C, Soriano P, Mundy GR. Requirement of pp60c-src expression for osteoclasts to form ruffled borders and resorb bone in mice. J Clin Invest. 90:1622–1627. 1992.

10. Faccio R, Takeshita S, Zallone A, Ross FP, Teitelbaum SL. c-Fms and the alphavbeta3 integrin collaborate during osteoclast differentiation. J Clin Invest. 111:749–758. 2003.

11. Yoshida H, Hayashi S, Kunisada T, Ogawa M, Nishikawa S, Okamura H, Sudo T, Shultz LD, Nishikawa S. The murine mutation osteopetrosis is in the coding region of the macrophage colony stimulating factor gene. Nature. 345:442–444. 1990.

12. Wiktor-Jedrzej czak W, Bartocci A, Ferrante AW Jr, Ahmed-Ansari A, Sell KW, Pollard JW, Stanley ER. Total absence of colony-stimulating factor 1 in the macrophage-deficient osteopetrotic (op/op) mouse. Proc Natl Acad Sci U S A. 87:4828–4832. 1990.

13. Silver IA, Murrills RJ, Etherington DJ. Microelectrode studies on the acid microenvironment beneath adherent macrophages and osteoclasts. Exp Cell Res. 175:266–276. 1988.

14. Blair HC, Teitelbaum SL, Ghiselli R, Gluck S. Osteoclastic bone resorption by a polarized vacuolar proton pump. Science. 245:855–857. 1989.

15. Li YP, Chen W, Liang Y, Li E, Stashenko P. Atp6i-deficient mice exhibit severe osteopetrosis due to loss of osteoclast-mediated extracellular acidification. Nat Genet. 23:447–451. 1999.

16. Scimeca JC, Franchi A, Trojani C, Parrinello H, Grosgeorge J, Robert C, Jaillon O, Poirier C, Gaudray P, Carle GF. The gene encoding the mouse homologue of the human osteoclast-specific 116-kDa V-ATPase subunit bears a deletion in osteosclerotic (oc/oc) mutants. Bone. 26:207–213. 2000.

17. Frattini A, Orchard PJ, Sobacchi C, Giliani S, Abinun M, Mattsson JP, Keeling DJ, Andersson AK, Wallbrandt P, Zecca L, Notarangelo LD, Vezzoni P, Villa A. Defects in TCIRG1 subunit of the vacuolar proton pump are responsible for a subset of human autosomal recessive osteopetrosis. Nat Genet. 25:343–346. 2000.

18. Kornak U, Schulz A, Friedrich W, Uhlhaas S, Kremens B, Voit T, Hasan C, Bode U, Jentsch TJ, Kubisch C. Mutations in the a3 subunit of the vacuolar H(+)-ATPase cause infantile malignant osteopetrosis. Hum Mol Genet. 9:2059–2063. 2000.

19. Anderson RE, Schraer H, Gay CV. Ultrastructural immunocytochemical localization of carbonic anhydrase in normal and calcitonin treated chick osteoclasts. Anat Rec. 204:9–20. 1982.

20. Laitala T, Väänänen HK. Inhibition of bone resorption in vitro by antisense RNA and DNA molecules targeted against carbonic anhydrase II or two subunits of vacuolar H(+)-ATPase. J Clin Invest. 93:2311–2318. 1994.

21. Minkin C, Jennings JM. Carbonic anhydrase and bone remodeling: sulfonamide inhibition of bone resorption in organ culture. Science. 176:10311033. 1972.

22. Sly WS, Whyte MP, Sundaram V, Tashian RE, Hewett-Emmett D, Guibaud P, Vainsel M, Baluarte HJ, Gruskin A, Al-Mosawi M, Sakati N, Ohlsson A. Carbonic anhydrase II deficiency in 12 families with the autosomal recessive syndrome of osteopetrosis with renal tubular acidosis and cerebral calcification. N Engl J Med. 313:139–145. 1985.

23. Tezuka K, Tezuka Y, Maejima A, Sato T, Nemoto K, Kamioka H, Hakeda Y, Kumegawa M. Molecular cloning of a possible cysteine proteinase predominantly expressed in osteoclasts. J Biol Chem. 269:1106–1109. 1994.

24. Drake FH, James IE, Connor JR, Rieman D, Dodds RA, McCabe F, Bertolini D, Barthlow R, Hastings G, Gowen M. Identification of a novel osteoclast-selective human cysteine proteinase. J Bone Miner Res. 9:S177. 1994.

25. Inaoka T, Bilbe G, Ishibashi O, Tezuka K, Kumegawa M, Kokubo T. Molecular cloning of human cDNA for cathepsin K: novel cysteine proteinase predominantly expressed in bone. Biochem Biophys Res Commun. 206:89–96. 1995.

26. 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. Cathepsin K knockout mice develop osteopetrosis due to a deficit in matrix degradation but not demoralization. J Bone Miner Res. 14:1654–1663. 1999.

27. Gelb BD, Shi GP, Chapman HA, Desnick RJ. Pycnodysostosis, a lysosomal disease caused by cathepsin K deficiency Science. 273:1236–1238. 1996.

28. Johnson MR, Polymeropoulos MH, Vos HL, Ortiz de Luna RI, Francomano CA. A nonsense mutation in the cathepsin K gene observed in a family with pycnodysostosis. Genome Res. 6:1050–1055. 1996.

29. Roberts HC, Knott L, Avery NC, Cox TM, Evans MJ, Hayman AR. Altered collagen in tartrate-resistant acid phosphatase (TRAP)-deficient mice: a role for TRAP in bone collagen metabolism. Calcif Tissue Int. 80:400–410. 2007.

30. Picollo A, Pusch M. Chloride/proton antiporter activity of mammalian CLC proteins ClC-4 and ClC-5. Nature. 436:420–423. 2005.

31. Kornak U, Kasper D, Bösl MR, Kaiser E, Schweizer M, Schulz A, Friedrich W, Delling G, Jentsch TJ. Loss of the C1C–7 chloride channel leads to osteopetrosis in mice and man. Cell. 104:205–215. 2001.

32. Anderson DM, Maraskovsky E, Billingsley WL, Dougall WC, Tometsko ME, Roux ER, Teepe MC, DuBose RF, Cosman D, Galibert L. A homologue of the TNF receptor and its ligand enhance T-cell growth and dendritic-cell function. Nature. 390:175–179. 1997.

33. Khosla S. Minireview: the OPG/RANKL/RANK system. Endocrinology. 142:5050–5055. 2001.

34. Wong BR, Josien R, Lee SY, Sauter B, Li HL, Steinman RM, Choi Y. TRANCE (tumor necrosis factor [TNF]-related activation-induced cytokine), a new TNF family member predominantly expressed in T cells, is a dendritic cell-specific survival factor. J Exp Med. 186:2075–2080. 1997.

35. Simonet WS, Lacey DL, Dunstan CR, Kelley M, Chang MS, Lüthy R, Nguyen HQ, Wooden S, Bennett L, Boone T, Shimamoto G, DeRose M, Elliott R, Colombero A, Tan HL, Trail G, Sullivan J, Davy E, Bucay N, Renshaw-Gegg L, Hughes TM, Hill D, Pattison W, Campbell P, Sander S, Van G, Tarpley J, Derby P, Lee R, Boyle WJ. Osteoprotegerin: a novel secreted protein involved in the regulation of bone density. Cell. 89:309–319. 1997.

36. 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. OPGL is a key regulator of osteoclastogenesis, lymphocyte development and lymph-node organogenesis. Nature. 397:315–323. 1999.

37. Marx J. Coming to grips with bone loss. Science. 305:1420–1422. 2004.

38. Bucay N, Sarosi I, Dunstan CR, Morony S, Tarpley J, Capparelli C, Scully S, Tan HL, Xu W, Lacey DL, Boyle WJ, Simonet WS. osteoprotegerin-deficient mice develop early onset osteoporosis and arterial calcification. Genes Dev. 12:1260–1268. 1998.

39. Tondravi MM, McKercher SR, Anderson K, Erdmann JM, Quiroz M, Maki R, Teitelbaum SL. Osteopetrosis in mice lacking haematopoietic transcription factor PU.1. Nature. 386:81–84. 1997.

40. Kwon OH, Lee CK, Lee YI, Paik SG, Lee HJ. The hematopoietic transcription factor PU.1 regulates RANK gene expression in myeloid progenitors. Biochem Biophys Res Commun. 335:437–446. 2005.

41. Luchin A, Suchting S, Merson T, Rosol TJ, Hume DA, Cassady AI, Ostrowski MC. Genetic and physical interactions between Microphthalmia transcription factor and PU.1 are necessary for osteoclast gene expression and differentiation. J Biol Chem. 276:36703–36710. 2001.

42. So H, Rho J, Jeong D, Park R, Fisher DE, Ostrowski MC, Choi Y, Kim N. Microphthalmia transcription factor and PU.1 synergistically induce the leukocyte receptor osteoclast-associated receptor gene expression. J Biol Chem. 278:24209–24216. 2003.

43. Sharma SM, Bronisz A, Hu R, Patel K, Mansky KC, Sif S, Ostrowski MC. MITF and PU.1 recruit p38 MAPK and NFATc1 to target genes during osteoclast differentiation. J Biol Chem. 282:15921–15929. 2007.

44. Grigoriadis AE, Wang ZQ, Cecchini MG, Hofstetter W, Felix R, Fleisch HA, Wagner EF. c-Fos: a key regulator of osteoclastmacrophage lineage determination and bone remodeling. Science. 266:443–448. 1994.

45. Matsuo K, Owens JM, Tonko M, Elliott C, Chambers TJ, Wagner EF. Fosl1 is a transcriptional target of c-Fos during osteoclast differentiation. Nat Genet. 24:184–187. 2000.

46. Fleischmann A, Hafezi F, Elliott C, Remé CE, Rüther U, Wagner EF. Fra-1 replaces c-Fos-dependent functions in mice. Genes Dev. 14:2695–2700. 2000.

47. Iotsova V, Caamaño J, Loy J, Yang Y, Lewin A, Bravo R. Osteopetrosis in mice lacking NF-kappaB1 and NF-kappaB2. Nat Med. 3:1285–1289. 1997.

48. Franzoso G, Carlson L, Xing L, Poljak L, Shores EW, Brown KD, Leonardi A, Tran T, Boyce BF, Siebenlist U. Requirement for NF-kappaB in osteoclast and B-cell development. Genes Dev. 11:3482–3496. 1997.

49. Xing L, Bushnell TP, Carlson L, Tai Z, Tondravi M, Siebenlist U, Young F, Boyce BF. NF-kappaB p50 and p52 expression is not required for RANK-expressing osteoclast progenitor formation but is essential for RANK- and cytokinemediated osteoclastogenesis. J Bone Miner Res. 17:1200–1210. 2002.

50. Yamashita T, Yao Z, Li F, Zhang Q, Badell IR, Schwarz EM, Takeshita S, Wagner EF, Noda M, Matsuo K, Xing L, Boyce BF. NF-kappaB p50 and p52 regulate receptor activator of NF-kappaB ligand (RANKL) and tumor necrosis factor-induced osteoclast precursor differentiation by activating c-Fos and NFATc1. J Biol Chem. 282:18245–18253. 2007.

51. 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. Induction and activation of the transcription factor NFATc1 (NFAT2) integrate RANKL signaling in terminal differentiation of osteoclasts. Dev Cell. 3:889–901. 2002.

52. Zhou P, Sun LJ, Dötsch V, Wagner G, Verdine GL. Solution structure of the core NFATC1/DNA complex. Cell. 92:687–696. 1998.

53. Matsumoto M, Kogawa M, Wada S, Takayanagi H, Tsujimoto M, Katayama S, Hisatake K, Nogi Y. Essential role of p38 mitogen-activated protein kinase in cathepsin K gene expression during osteoclastogenesis through association of NFATc1 and PU.1. J Biol Chem. 279:45969–45979. 2004.

54. Gohda J, Akiyama T, Koga T, Takayanagi H, Tanaka S, Inoue J. RANKmediated amplification of TRAF6 signaling leads to NFATc1 induction during osteoclastogenesis. EMBO J. 24:790–799. 2005.

55. Asagiri M, Sato K, Usami T, Ochi S, Nishina H, Yoshida H, Morita I, Wagner EF, Mak TW, Serflling E, Takayanagi H. Autoamplification of NFATc1 expression determines its essential role in bone homeostasis. J Exp Med. 202:1261–1269. 2005.

56. Song I, Kim JH, Kim K, Jin HM, Youn BU, Kim N. Regulatory mechanism of NFATc1 in RANKL-induced osteoclast activation. FEBS Lett. 583:2435–2440. 2009.

57. Kuroda Y, Hisatsune C, Nakamura T, Matsuo K, Mikoshiba K. Osteoblasts induce Ca2+oscillation-independent NFATc1 activation during osteoclastogenesis. Proc Natl Acad Sci U S A. 105:8643–8648. 2008.

58. Feng H, Cheng T, Steer JH, Joyce DA, Pavlos NJ, Leong C, Kular J, Liu J, Feng X, Zheng MH, Xu J. Myocyte enhancer factor2 and microphthalmia-associated transcription factor cooperate with NFATc 1 to transactivate the V-ATPase d2 promoter during RANKL-induced osteoclastogenesis. J Biol Chem. 284:14667–14676. 2009.

59. Kim K, Lee SH, Kim JH, Choi Y, Kim N. NFATc1 induces osteoclast fusion via upregulation of Atp6v0d2 and the dendritic cell-specific transmembrane protein (DC-STAMP). Mol Endocrinol. 22:176–185. 2008.

60. Mansky KC, Sankar U, Han J, Ostrowski MC. Microphthalmia transcription factor is a target of the p38 MAPK pathway in response to receptor activator of NF-kappa B ligand signaling. J Biol Chem. 277:11077–11083. 2002.

61. Kim JH, Jin HM, Kim K, Song I, Youn BU, Matsuo K, Kim N. The mechanism of osteoclast differentiation induced by IL-1. J Immunol. 183:1862–1870. 2009.

62. Luchin A, Purdom G, Murphy K, Clark MY, Angel N, Cassady AI, Hume DA, Ostrowski MC. The microphthalmia transcription factor regulates expression of the tartrate-resistant acid phosphatase gene during terminal differentiation of osteoclasts. J Bone Miner Res. 15:451–460. 2000.