2,470
Views
60
CrossRef citations to date
0
Altmetric
Review

Modulation of osteoclast differentiation and bone resorption by Rho GTPases

, &
Article: e28119 | Received 11 Oct 2013, Accepted 05 Feb 2014, Published online: 10 Mar 2014

References

  • Sims NA, Gooi JH. Bone remodeling: Multiple cellular interactions required for coupling of bone formation and resorption. Semin Cell Dev Biol 2008; 19:444 - 51; http://dx.doi.org/10.1016/j.semcdb.2008.07.016; PMID: 18718546
  • Matsuo K, Irie N. Osteoclast-osteoblast communication. Arch Biochem Biophys 2008; 473:201 - 9; http://dx.doi.org/10.1016/j.abb.2008.03.027; PMID: 18406338
  • Lacey DL, Boyle WJ, Simonet WS, Kostenuik PJ, Dougall WC, Sullivan JK, San Martin J, Dansey R. Bench to bedside: elucidation of the OPG-RANK-RANKL pathway and the development of denosumab. Nat Rev Drug Discov 2012; 11:401 - 19; http://dx.doi.org/10.1038/nrd3705; PMID: 22543469
  • Hall A. Rho family GTPases. Biochem Soc Trans 2012; 40:1378 - 82; http://dx.doi.org/10.1042/BST20120103; PMID: 23176484
  • Rossman KL, Der CJ, Sondek J. GEF means go: turning on RHO GTPases with guanine nucleotide-exchange factors. Nat Rev Mol Cell Biol 2005; 6:167 - 80; http://dx.doi.org/10.1038/nrm1587; PMID: 15688002
  • Ihara K, Muraguchi S, Kato M, Shimizu T, Shirakawa M, Kuroda S, Kaibuchi K, Hakoshima T. Crystal structure of human RhoA in a dominantly active form complexed with a GTP analogue. J Biol Chem 1998; 273:9656 - 66; http://dx.doi.org/10.1074/jbc.273.16.9656; PMID: 9545299
  • Zhang B, Chernoff J, Zheng Y. Interaction of Rac1 with GTPase-activating proteins and putative effectors. A comparison with Cdc42 and RhoA. J Biol Chem 1998; 273:8776 - 82; http://dx.doi.org/10.1074/jbc.273.15.8776; PMID: 9535855
  • Cherfils J, Zeghouf M. Regulation of small GTPases by GEFs, GAPs, and GDIs. Physiol Rev 2013; 93:269 - 309; http://dx.doi.org/10.1152/physrev.00003.2012; PMID: 23303910
  • Aspenström P, Ruusala A, Pacholsky D. Taking Rho GTPases to the next level: the cellular functions of atypical Rho GTPases. Exp Cell Res 2007; 313:3673 - 9; http://dx.doi.org/10.1016/j.yexcr.2007.07.022; PMID: 17850788
  • Zhang DE, Hetherington CJ, Chen HM, Tenen DG. The macrophage transcription factor PU.1 directs tissue-specific expression of the macrophage colony-stimulating factor receptor. Mol Cell Biol 1994; 14:373 - 81; PMID: 8264604
  • Yoshida S, Setoguchi M, Higuchi Y, Akizuki S, Yamamoto S. Molecular cloning of cDNA encoding MS2 antigen, a novel cell surface antigen strongly expressed in murine monocytic lineage. Int Immunol 1990; 2:585 - 91; http://dx.doi.org/10.1093/intimm/2.6.585; PMID: 1982220
  • Ross FP, Teitelbaum SL. alphavbeta3 and macrophage colony-stimulating factor: partners in osteoclast biology. Immunol Rev 2005; 208:88 - 105; http://dx.doi.org/10.1111/j.0105-2896.2005.00331.x; PMID: 16313343
  • Ito Y, Teitelbaum SL, Zou W, Zheng Y, Johnson JF, Chappel J, Ross FP, Zhao H. Cdc42 regulates bone modeling and remodeling in mice by modulating RANKL/M-CSF signaling and osteoclast polarization. J Clin Invest 2010; 120:1981 - 93; http://dx.doi.org/10.1172/JCI39650; PMID: 20501942
  • Yavropoulou MP, Yovos JG. Osteoclastogenesis--current knowledge and future perspectives. J Musculoskelet Neuronal Interact 2008; 8:204 - 16; PMID: 18799853
  • Paternot S, Bockstaele L, Bisteau X, Kooken H, Coulonval K, Roger PP. Rb inactivation in cell cycle and cancer: the puzzle of highly regulated activating phosphorylation of CDK4 versus constitutively active CDK-activating kinase. Cell Cycle 2010; 9:689 - 99; http://dx.doi.org/10.4161/cc.9.4.10611; PMID: 20107323
  • Arai F, Miyamoto T, Ohneda O, Inada T, Sudo T, Brasel K, Miyata T, Anderson DM, Suda T. Commitment and differentiation of osteoclast precursor cells by the sequential expression of c-Fms and receptor activator of nuclear factor kappaB (RANK) receptors. J Exp Med 1999; 190:1741 - 54; http://dx.doi.org/10.1084/jem.190.12.1741; PMID: 10601350
  • Ogasawara T, Katagiri M, Yamamoto A, Hoshi K, Takato T, Nakamura K, Tanaka S, Okayama H, Kawaguchi H. Osteoclast differentiation by RANKL requires NFkappaB-mediated downregulation of cyclin-dependent kinase 6 (Cdk6). J Bone Miner Res 2004; 19:1128 - 36; http://dx.doi.org/10.1359/jbmr.2004.19.7.1128; PMID: 15176996
  • Nakashima T, Hayashi M, Fukunaga T, Kurata K, Oh-Hora M, Feng JQ, Bonewald LF, Kodama T, Wutz A, Wagner EF, et al. Evidence for osteocyte regulation of bone homeostasis through RANKL expression. Nat Med 2011; 17:1231 - 4; http://dx.doi.org/10.1038/nm.2452; PMID: 21909105
  • Xiong J, Onal M, Jilka RL, Weinstein RS, Manolagas SC, O’Brien CA. Matrix-embedded cells control osteoclast formation. Nat Med 2011; 17:1235 - 41; http://dx.doi.org/10.1038/nm.2448; PMID: 21909103
  • Lee NK, Choi HK, Kim D-K, Lee SY. Rac1 GTPase regulates osteoclast differentiation through TRANCE-induced NFkappa B activation. Mol Cell Biochem 2006; 281:55 - 61; http://dx.doi.org/10.1007/s11010-006-0333-y; PMID: 16328957
  • Mizukami J, Takaesu G, Akatsuka H, Sakurai H, Ninomiya-Tsuji J, Matsumoto K, Sakurai N. Receptor activator of NFkappaB ligand (RANKL) activates TAK1 mitogen-activated protein kinase kinase kinase through a signaling complex containing RANK, TAB2, and TRAF6. Mol Cell Biol 2002; 22:992 - 1000; http://dx.doi.org/10.1128/MCB.22.4.992-1000.2002; PMID: 11809792
  • Besse A, Lamothe B, Campos AD, Webster WK, Maddineni U, Lin S-C, Wu H, Darnay BG. TAK1-dependent signaling requires functional interaction with TAB2/TAB3. J Biol Chem 2007; 282:3918 - 28; http://dx.doi.org/10.1074/jbc.M608867200; PMID: 17158449
  • Wang C, Deng L, Hong M, Akkaraju GR, Inoue J, Chen ZJ. TAK1 is a ubiquitin-dependent kinase of MKK and IKK. Nature 2001; 412:346 - 51; http://dx.doi.org/10.1038/35085597; PMID: 11460167
  • Lamothe B, Lai Y, Xie M, Schneider MD, Darnay BG. TAK1 is essential for osteoclast differentiation and is an important modulator of cell death by apoptosis and necroptosis. Mol Cell Biol 2013; 33:582 - 95; http://dx.doi.org/10.1128/MCB.01225-12; PMID: 23166301
  • Negishi-Koga T, Takayanagi H. Ca2+-NFATc1 signaling is an essential axis of osteoclast differentiation. Immunol Rev 2009; 231:241 - 56; http://dx.doi.org/10.1111/j.1600-065X.2009.00821.x; PMID: 19754901
  • Koga T, Inui M, Inoue K, Kim S, Suematsu A, Kobayashi E, Iwata T, Ohnishi H, Matozaki T, Kodama T, et al. Costimulatory signals mediated by the ITAM motif cooperate with RANKL for bone homeostasis. Nature 2004; 428:758 - 63; http://dx.doi.org/10.1038/nature02444; PMID: 15085135
  • Asagiri M, Sato K, Usami T, Ochi S, Nishina H, Yoshida H, Morita I, Wagner EF, Mak TW, Serfling E, et al. Autoamplification of NFATc1 expression determines its essential role in bone homeostasis. J Exp Med 2005; 202:1261 - 9; http://dx.doi.org/10.1084/jem.20051150; PMID: 16275763
  • Danks L, Takayanagi H. Immunology and bone. J Biochem 2013; 154:29 - 39; http://dx.doi.org/10.1093/jb/mvt049; PMID: 23750028
  • Lee NK, Choi YG, Baik JY, Han SY, Jeong D-W, Bae YS, Kim N, Lee SY. A crucial role for reactive oxygen species in RANKL-induced osteoclast differentiation. Blood 2005; 106:852 - 9; http://dx.doi.org/10.1182/blood-2004-09-3662; PMID: 15817678
  • Kim MS, Yang Y-M, Son A, Tian YS, Lee S-I, Kang SW, Muallem S, Shin DM. RANKL-mediated reactive oxygen species pathway that induces long lasting Ca2+ oscillations essential for osteoclastogenesis. J Biol Chem 2010; 285:6913 - 21; http://dx.doi.org/10.1074/jbc.M109.051557; PMID: 20048168
  • Wang Y, Lebowitz D, Sun C, Thang H, Grynpas MD, Glogauer M. Identifying the relative contributions of Rac1 and Rac2 to osteoclastogenesis. J Bone Miner Res 2008; 23:260 - 70; http://dx.doi.org/10.1359/jbmr.071013; PMID: 17922611
  • Asagiri M, Takayanagi H. The molecular understanding of osteoclast differentiation. Bone 2007; 40:251 - 64; http://dx.doi.org/10.1016/j.bone.2006.09.023; PMID: 17098490
  • Feng H, Cheng T, Steer JH, Joyce DA, Pavlos NJ, Leong C, Kular J, Liu J, Feng X, Zheng MH, et al. Myocyte enhancer factor 2 and microphthalmia-associated transcription factor cooperate with NFATc1 to transactivate the V-ATPase d2 promoter during RANKL-induced osteoclastogenesis. J Biol Chem 2009; 284:14667 - 76; http://dx.doi.org/10.1074/jbc.M901670200; PMID: 19321441
  • Lu S-Y, Li M, Lin Y-L. Mitf induction by RANKL is critical for osteoclastogenesis. Mol Biol Cell 2010; 21:1763 - 71; http://dx.doi.org/10.1091/mbc.E09-07-0584; PMID: 20357005
  • 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 NFkappa B ligand signaling. J Biol Chem 2002; 277:11077 - 83; http://dx.doi.org/10.1074/jbc.M111696200; PMID: 11792706
  • 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 2007; 282:15921 - 9; http://dx.doi.org/10.1074/jbc.M609723200; PMID: 17403683
  • Gonzalo P, Guadamillas MC, Hernández-Riquer MV, Pollán A, Grande-García A, Bartolomé RA, Vasanji A, Ambrogio C, Chiarle R, Teixidó J, et al. MT1-MMP is required for myeloid cell fusion via regulation of Rac1 signaling. Dev Cell 2010; 18:77 - 89; http://dx.doi.org/10.1016/j.devcel.2009.11.012; PMID: 20152179
  • Leung R, Cuddy K, Wang Y, Rommens J, Glogauer M. Sbds is required for Rac2-mediated monocyte migration and signaling downstream of RANK during osteoclastogenesis. Blood 2011; 117:2044 - 53; http://dx.doi.org/10.1182/blood-2010-05-282574; PMID: 21084708
  • Leung R, Wang Y, Cuddy K, Sun C, Magalhaes J, Grynpas M, Glogauer M. Filamin A regulates monocyte migration through Rho small GTPases during osteoclastogenesis. J Bone Miner Res 2010; 25:1077 - 91; PMID: 19929439
  • Brazier H, Stephens S, Ory S, Fort P, Morrison N, Blangy A. Expression profile of RhoGTPases and RhoGEFs during RANKL-stimulated osteoclastogenesis: identification of essential genes in osteoclasts. J Bone Miner Res 2006; 21:1387 - 98; http://dx.doi.org/10.1359/jbmr.060613; PMID: 16939397
  • Tao W, Pennica D, Xu L, Kalejta RF, Levine AJ. Wrch-1, a novel member of the Rho gene family that is regulated by Wnt-1. Genes Dev 2001; 15:1796 - 807; http://dx.doi.org/10.1101/gad.894301; PMID: 11459829
  • Brazier H, Pawlak G, Vives V, Blangy A. The Rho GTPase Wrch1 regulates osteoclast precursor adhesion and migration. Int J Biochem Cell Biol 2009; 41:1391 - 401; http://dx.doi.org/10.1016/j.biocel.2008.12.007; PMID: 19135548
  • Saltel F, Destaing O, Bard F, Eichert D, Jurdic P. Apatite-mediated actin dynamics in resorbing osteoclasts. Mol Biol Cell 2004; 15:5231 - 41; http://dx.doi.org/10.1091/mbc.E04-06-0522; PMID: 15371537
  • Gil-Henn H, Destaing O, Sims NA, Aoki K, Alles N, Neff L, Sanjay A, Bruzzaniti A, De Camilli P, Baron R, et al. Defective microtubule-dependent podosome organization in osteoclasts leads to increased bone density in Pyk2(-/-) mice. J Cell Biol 2007; 178:1053 - 64; http://dx.doi.org/10.1083/jcb.200701148; PMID: 17846174
  • Soriano P, Montgomery C, Geske R, Bradley A. Targeted disruption of the c-src proto-oncogene leads to osteopetrosis in mice. Cell 1991; 64:693 - 702; http://dx.doi.org/10.1016/0092-8674(91)90499-O; PMID: 1997203
  • Qin A, Cheng TS, Pavlos NJ, Lin Z, Dai KR, Zheng MH. V-ATPases in osteoclasts: structure, function and potential inhibitors of bone resorption. Int J Biochem Cell Biol 2012; 44:1422 - 35; http://dx.doi.org/10.1016/j.biocel.2012.05.014; PMID: 22652318
  • Saltel F, Destaing O, Bard F, Eichert D, Jurdic P. Apatite-mediated actin dynamics in resorbing osteoclasts. Mol Biol Cell 2004; 15:5231 - 41; http://dx.doi.org/10.1091/mbc.E04-06-0522; PMID: 15371537
  • Ory S, Brazier H, Pawlak G, Blangy A. Rho GTPases in osteoclasts: orchestrators of podosome arrangement. Eur J Cell Biol 2008; 87:469 - 77; http://dx.doi.org/10.1016/j.ejcb.2008.03.002; PMID: 18436334
  • Jurdic P, Saltel F, Chabadel A, Destaing O. Podosome and sealing zone: specificity of the osteoclast model. Eur J Cell Biol 2006; 85:195 - 202; http://dx.doi.org/10.1016/j.ejcb.2005.09.008; PMID: 16546562
  • Luxenburg C, Geblinger D, Klein E, Anderson K, Hanein D, Geiger B, Addadi L. The architecture of the adhesive apparatus of cultured osteoclasts: from podosome formation to sealing zone assembly. PLoS One 2007; 2:e179; http://dx.doi.org/10.1371/journal.pone.0000179; PMID: 17264882
  • Jurdic P, Saltel F, Chabadel A, Destaing O. Podosome and sealing zone: specificity of the osteoclast model. Eur J Cell Biol 2006; 85:195 - 202; http://dx.doi.org/10.1016/j.ejcb.2005.09.008; PMID: 16546562
  • Chabadel A, Bañon-Rodríguez I, Cluet D, Rudkin BB, Wehrle-Haller B, Genot E, Jurdic P, Anton IM, Saltel F. CD44 and beta3 integrin organize two functionally distinct actin-based domains in osteoclasts. Mol Biol Cell 2007; 18:4899 - 910; http://dx.doi.org/10.1091/mbc.E07-04-0378; PMID: 17898081
  • Chellaiah MA, Kizer N, Biswas R, Alvarez U, Strauss-Schoenberger J, Rifas L, Rittling SR, Denhardt DT, Hruska KA. Osteopontin deficiency produces osteoclast dysfunction due to reduced CD44 surface expression. Mol Biol Cell 2003; 14:173 - 89; http://dx.doi.org/10.1091/mbc.E02-06-0354; PMID: 12529435
  • 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 2000; 105:433 - 40; http://dx.doi.org/10.1172/JCI8905; PMID: 10683372
  • Destaing O, Sanjay A, Itzstein C, Horne WC, Toomre D, De Camilli P, Baron R. The tyrosine kinase activity of c-Src regulates actin dynamics and organization of podosomes in osteoclasts. Mol Biol Cell 2008; 19:394 - 404; http://dx.doi.org/10.1091/mbc.E07-03-0227; PMID: 17978100
  • Nagai Y, Osawa K, Fukushima H, Tamura Y, Aoki K, Ohya K, Yasuda H, Hikiji H, Takahashi M, Seta Y, et al. p130Cas, Crk-associated substrate, plays important roles in osteoclastic bone resorption. J Bone Miner Res 2013; 28:2449 - 62; http://dx.doi.org/10.1002/jbmr.1936; PMID: 23526406
  • Faccio R, Novack DV, Zallone A, Ross FP, Teitelbaum SL. Dynamic changes in the osteoclast cytoskeleton in response to growth factors and cell attachment are controlled by beta3 integrin. J Cell Biol 2003; 162:499 - 509; http://dx.doi.org/10.1083/jcb.200212082; PMID: 12900398
  • Zhang D, Udagawa N, Nakamura I, Murakami H, Saito S, Yamasaki K, Shibasaki Y, Morii N, Narumiya S, Takahashi N, et al. The small GTP-binding protein, rho p21, is involved in bone resorption by regulating cytoskeletal organization in osteoclasts. J Cell Sci 1995; 108:2285 - 92; PMID: 7673348
  • Ory S, Munari-Silem Y, Fort P, Jurdic P. Rho and Rac exert antagonistic functions on spreading of macrophage-derived multinucleated cells and are not required for actin fiber formation. J Cell Sci 2000; 113:1177 - 88; PMID: 10704369
  • Chellaiah MA, Soga N, Swanson S, McAllister S, Alvarez U, Wang D, Dowdy SF, Hruska KA. Rho-A is critical for osteoclast podosome organization, motility, and bone resorption. J Biol Chem 2000; 275:11993 - 2002; http://dx.doi.org/10.1074/jbc.275.16.11993; PMID: 10766830
  • Destaing O, Saltel F, Gilquin B, Chabadel A, Khochbin S, Ory S, Jurdic P. A novel Rho-mDia2-HDAC6 pathway controls podosome patterning through microtubule acetylation in osteoclasts. J Cell Sci 2005; 118:2901 - 11; http://dx.doi.org/10.1242/jcs.02425; PMID: 15976449
  • Palazzo AF, Cook TA, Alberts AS, Gundersen GG. mDia mediates Rho-regulated formation and orientation of stable microtubules. Nat Cell Biol 2001; 3:723 - 9; http://dx.doi.org/10.1038/35087035; PMID: 11483957
  • Croke M, Ross FP, Korhonen M, Williams DA, Zou W, Teitelbaum SL. Rac deletion in osteoclasts causes severe osteopetrosis. J Cell Sci 2011; 124:3811 - 21; http://dx.doi.org/10.1242/jcs.086280; PMID: 22114304
  • Itokowa T, Zhu ML, Troiano N, Bian J, Kawano T, Insogna K. Osteoclasts lacking Rac2 have defective chemotaxis and resorptive activity. Calcif Tissue Int 2011; 88:75 - 86; http://dx.doi.org/10.1007/s00223-010-9435-3; PMID: 21110188
  • Magalhaes JKRS, Grynpas MD, Willett TL, Glogauer M. Deleting Rac1 improves vertebral bone quality and resistance to fracture in a murine ovariectomy model. Osteoporos Int 2011; 22:1481 - 92; http://dx.doi.org/10.1007/s00198-010-1355-6; PMID: 20683708
  • Goldberg SR, Georgiou J, Glogauer M, Grynpas MD. A 3D scanning confocal imaging method measures pit volume and captures the role of Rac in osteoclast function. Bone 2012; 51:145 - 52; http://dx.doi.org/10.1016/j.bone.2012.04.018; PMID: 22561898
  • Razzouk S, Lieberherr M, Cournot G. Rac-GTPase, osteoclast cytoskeleton and bone resorption. Eur J Cell Biol 1999; 78:249 - 55; http://dx.doi.org/10.1016/S0171-9335(99)80058-2; PMID: 10350213
  • Faccio R, Teitelbaum SL, Fujikawa K, Chappel J, Zallone A, Tybulewicz VL, Ross FP, Swat W. Vav3 regulates osteoclast function and bone mass. Nat Med 2005; 11:284 - 90; http://dx.doi.org/10.1038/nm1194; PMID: 15711558
  • Takegahara N, Kang S, Nojima S, Takamatsu H, Okuno T, Kikutani H, Toyofuku T, Kumanogoh A. Integral roles of a guanine nucleotide exchange factor, FARP2, in osteoclast podosome rearrangements. FASEB J 2010; 24:4782 - 92; http://dx.doi.org/10.1096/fj.10-158212; PMID: 20702777
  • Vives V, Laurin M, Cres G, Larrousse P, Morichaud Z, Noel D, Côté J-F, Blangy A. The Rac1 exchange factor Dock5 is essential for bone resorption by osteoclasts. J Bone Miner Res 2011; 26:1099 - 110; http://dx.doi.org/10.1002/jbmr.282; PMID: 21542010
  • Sakai H, Chen Y, Itokawa T, Yu K-P, Zhu M-L, Insogna K. Activated c-Fms recruits Vav and Rac during CSF-1-induced cytoskeletal remodeling and spreading in osteoclasts. Bone 2006; 39:1290 - 301; http://dx.doi.org/10.1016/j.bone.2006.06.012; PMID: 16950670
  • Destaing O, Saltel F, Géminard J-C, Jurdic P, Bard F. Podosomes display actin turnover and dynamic self-organization in osteoclasts expressing actin-green fluorescent protein. Mol Biol Cell 2003; 14:407 - 16; http://dx.doi.org/10.1091/mbc.E02-07-0389; PMID: 12589043
  • Campellone KG, Welch MD. A nucleator arms race: cellular control of actin assembly. Nat Rev Mol Cell Biol 2010; 11:237 - 51; http://dx.doi.org/10.1038/nrm2867; PMID: 20237478
  • Ho H-YH, Rohatgi R, Lebensohn AM, Le Ma, Li J, Gygi SP, Kirschner MW. Toca-1 mediates Cdc42-dependent actin nucleation by activating the N-WASP-WIP complex. Cell 2004; 118:203 - 16; http://dx.doi.org/10.1016/j.cell.2004.06.027; PMID: 15260990
  • Chellaiah MA. Regulation of actin ring formation by rho GTPases in osteoclasts. J Biol Chem 2005; 280:32930 - 43; http://dx.doi.org/10.1074/jbc.M500154200; PMID: 16006560
  • Buck M, Xu W, Rosen MK. Global disruption of the WASP autoinhibited structure on Cdc42 binding. Ligand displacement as a novel method for monitoring amide hydrogen exchange. Biochemistry 2001; 40:14115 - 22; http://dx.doi.org/10.1021/bi0157215; PMID: 11714264
  • Torres E, Rosen MK. Contingent phosphorylation/dephosphorylation provides a mechanism of molecular memory in WASP. Mol Cell 2003; 11:1215 - 27; http://dx.doi.org/10.1016/S1097-2765(03)00139-4; PMID: 12769846
  • Ma T, Samanna V, Chellaiah MA. Dramatic inhibition of osteoclast sealing ring formation and bone resorption in vitro by a WASP-peptide containing pTyr294 amino acid. J Mol Signal 2008; 3:4; http://dx.doi.org/10.1186/1750-2187-3-4; PMID: 18289379
  • Calle Y, Jones GE, Jagger C, Fuller K, Blundell MP, Chow J, Chambers T, Thrasher AJ. WASp deficiency in mice results in failure to form osteoclast sealing zones and defects in bone resorption. Blood 2004; 103:3552 - 61; http://dx.doi.org/10.1182/blood-2003-04-1259; PMID: 14726392
  • Abdul-Manan N, Aghazadeh B, Liu GA, Majumdar A, Ouerfelli O, Siminovitch KA, Rosen MK. Structure of Cdc42 in complex with the GTPase-binding domain of the ‘Wiskott-Aldrich syndrome’ protein. Nature 1999; 399:379 - 83; http://dx.doi.org/10.1038/20726; PMID: 10360578
  • Rohatgi R, Ma L, Miki H, Lopez M, Kirchhausen T, Takenawa T, Kirschner MW. The interaction between N-WASP and the Arp2/3 complex links Cdc42-dependent signals to actin assembly. Cell 1999; 97:221 - 31; http://dx.doi.org/10.1016/S0092-8674(00)80732-1; PMID: 10219243
  • Georgess D, Mazzorana M, Terrado J, Delprat C, Chamot C, Guasch RM, Pérez-Roger I, Jurdic P, Machuca-Gayet I. Comparative transcriptomics reveals RhoE as a novel regulator of actin dynamics in bone-resorbing osteoclasts. Mol Biol Cell 2014; 25:380 - 96; http://dx.doi.org/10.1091/mbc.E13-07-0363; PMID: 24284899
  • Blangy A, Touaitahuata H, Cres G, Pawlak G. Cofilin activation during podosome belt formation in osteoclasts. PLoS One 2012; 7:e45909; http://dx.doi.org/10.1371/journal.pone.0045909; PMID: 23049890
  • Lebensohn AM, Kirschner MW. Activation of the WAVE complex by coincident signals controls actin assembly. Mol Cell 2009; 36:512 - 24; http://dx.doi.org/10.1016/j.molcel.2009.10.024; PMID: 19917258
  • Mulari M, Vääräniemi J, Väänänen HK. Intracellular membrane trafficking in bone resorbing osteoclasts. Microsc Res Tech 2003; 61:496 - 503; http://dx.doi.org/10.1002/jemt.10371; PMID: 12879417
  • Itzstein C, Coxon FP, Rogers MJ. The regulation of osteoclast function and bone resorption by small GTPases. Small GTPases 2011; 2:117 - 30; http://dx.doi.org/10.4161/sgtp.2.3.16453; PMID: 21776413
  • Zhao H, Laitala-Leinonen T, Parikka V, Väänänen HK. Downregulation of small GTPase Rab7 impairs osteoclast polarization and bone resorption. J Biol Chem 2001; 276:39295 - 302; http://dx.doi.org/10.1074/jbc.M010999200; PMID: 11514537
  • Sun Y, Büki KG, Ettala O, Vääräniemi JP, Väänänen HK. Possible role of direct Rac1-Rab7 interaction in ruffled border formation of osteoclasts. J Biol Chem 2005; 280:32356 - 61; http://dx.doi.org/10.1074/jbc.M414213200; PMID: 16040606
  • Lacombe J, Karsenty G, Ferron M. Regulation of lysosome biogenesis and functions in osteoclasts. Cell Cycle 2013; 12:2744 - 52; http://dx.doi.org/10.4161/cc.25825; PMID: 23966172
  • Joberty G, Petersen C, Gao L, Macara IG. The cell-polarity protein Par6 links Par3 and atypical protein kinase C to Cdc42. Nat Cell Biol 2000; 2:531 - 9; http://dx.doi.org/10.1038/35019573; PMID: 10934474
  • Nance J, Zallen JA. Elaborating polarity: PAR proteins and the cytoskeleton. Development 2011; 138:799 - 809; http://dx.doi.org/10.1242/dev.053538; PMID: 21303844
  • Faccio R, Teitelbaum SL, Fujikawa K, Chappel J, Zallone A, Tybulewicz VL, Ross FP, Swat W. Vav3 regulates osteoclast function and bone mass. Nat Med 2005; 11:284 - 90; http://dx.doi.org/10.1038/nm1194; PMID: 15711558
  • Fesik SW. Insights into programmed cell death through structural biology. Cell 2000; 103:273 - 82; http://dx.doi.org/10.1016/S0092-8674(00)00119-7; PMID: 11057900
  • Lee ZH, Lee SE, Kim C-W, Lee SH, Kim SW, Kwack K, Walsh K, Kim H-H. IL-1alpha stimulation of osteoclast survival through the PI 3-kinase/Akt and ERK pathways. J Biochem 2002; 131:161 - 6; http://dx.doi.org/10.1093/oxfordjournals.jbchem.a003071; PMID: 11754748
  • Lee SE, Chung WJ, Kwak HB, Chung CH, Kwack KB, Lee ZH, Kim HH. Tumor necrosis factor-alpha supports the survival of osteoclasts through the activation of Akt and ERK. J Biol Chem 2001; 276:49343 - 9; http://dx.doi.org/10.1074/jbc.M103642200; PMID: 11675379
  • Gingery A, Bradley E, Shaw A, Oursler MJ. Phosphatidylinositol 3-kinase coordinately activates the MEK/ERK and AKT/NFkappaB pathways to maintain osteoclast survival. J Cell Biochem 2003; 89:165 - 79; http://dx.doi.org/10.1002/jcb.10503; PMID: 12682917
  • Fukuda A, Hikita A, Wakeyama H, Akiyama T, Oda H, Nakamura K, Tanaka S. Regulation of osteoclast apoptosis and motility by small GTPase binding protein Rac1. J Bone Miner Res 2005; 20:2245 - 53; http://dx.doi.org/10.1359/JBMR.050816; PMID: 16294277
  • Armas LAG, Recker RR. Pathophysiology of osteoporosis: new mechanistic insights. Endocrinol Metab Clin North Am 2012; 41:475 - 86; http://dx.doi.org/10.1016/j.ecl.2012.04.006; PMID: 22877425
  • Chen Y-C, Sosnoski DM, Mastro AM. Breast cancer metastasis to the bone: mechanisms of bone loss. Breast Cancer Res 2010; 12:215; http://dx.doi.org/10.1186/bcr2781; PMID: 21176175
  • Russell RGG. Bisphosphonates: the first 40 years. Bone 2011; 49:2 - 19; http://dx.doi.org/10.1016/j.bone.2011.04.022; PMID: 21555003
  • Giger EV, Castagner B, Leroux J-C. Biomedical applications of bisphosphonates. J Control Release 2013; 167:175 - 88; http://dx.doi.org/10.1016/j.jconrel.2013.01.032; PMID: 23395668
  • Luckman SP, Coxon FP, Ebetino FH, Russell RG, Rogers MJ. Heterocycle-containing bisphosphonates cause apoptosis and inhibit bone resorption by preventing protein prenylation: evidence from structure-activity relationships in J774 macrophages. J Bone Miner Res 1998; 13:1668 - 78; http://dx.doi.org/10.1359/jbmr.1998.13.11.1668; PMID: 9797474
  • van Beek E, Pieterman E, Cohen L, Löwik C, Papapoulos S. Nitrogen-containing bisphosphonates inhibit isopentenyl pyrophosphate isomerase/farnesyl pyrophosphate synthase activity with relative potencies corresponding to their antiresorptive potencies in vitro and in vivo. Biochem Biophys Res Commun 1999; 255:491 - 4; http://dx.doi.org/10.1006/bbrc.1999.0224; PMID: 10049736
  • Coxon FP, Helfrich MH, Van’t Hof R, Sebti S, Ralston SH, Hamilton A, Rogers MJ. Protein geranylgeranylation is required for osteoclast formation, function, and survival: inhibition by bisphosphonates and GGTI-298. J Bone Miner Res 2000; 15:1467 - 76; http://dx.doi.org/10.1359/jbmr.2000.15.8.1467; PMID: 10934645
  • Dunford JE, Rogers MJ, Ebetino FH, Phipps RJ, Coxon FP. Inhibition of protein prenylation by bisphosphonates causes sustained activation of Rac, Cdc42, and Rho GTPases. J Bone Miner Res 2006; 21:684 - 94; http://dx.doi.org/10.1359/jbmr.060118; PMID: 16734383
  • Luckman SP, Hughes DE, Coxon FP, Graham R, Russell G, Rogers MJ. Nitrogen-containing bisphosphonates inhibit the mevalonate pathway and prevent post-translational prenylation of GTP-binding proteins, including Ras. J Bone Miner Res 1998; 13:581 - 9; http://dx.doi.org/10.1359/jbmr.1998.13.4.581; PMID: 9556058
  • Agarwal P, Rao NN. Bisphosphonate-associated osteonecrosis of the jaws. Indian J Dent Res 2012; 23:107 - 11; http://dx.doi.org/10.4103/0970-9290.99051; PMID: 22842261
  • Hirschberg R. Renal complications from bisphosphonate treatment. Curr Opin Support Palliat Care 2012; 6:342 - 7; http://dx.doi.org/10.1097/SPC.0b013e328356062e; PMID: 22710581
  • Lotinun S, Kiviranta R, Matsubara T, Alzate JA, Neff L, Lüth A, Koskivirta I, Kleuser B, Vacher J, Vuorio E, et al. Osteoclast-specific cathepsin K deletion stimulates S1P-dependent bone formation. J Clin Invest 2013; 123:666 - 81; PMID: 23321671
  • Motyckova G, Fisher DE. Pycnodysostosis: role and regulation of cathepsin K in osteoclast function and human disease. Curr Mol Med 2002; 2:407 - 21; http://dx.doi.org/10.2174/1566524023362401; PMID: 12125807
  • Chapurlat RD. Odanacatib for the treatment of postmenopausal osteoporosis. Expert Opin Pharmacother 2014; 15:97 - 102; http://dx.doi.org/10.1517/14656566.2014.853038; PMID: 24156249
  • Stoch SA, Zajic S, Stone JA, Miller DL, van Bortel L, Lasseter KC, Pramanik B, Cilissen C, Liu Q, Liu L, et al. Odanacatib, a selective cathepsin K inhibitor to treat osteoporosis: safety, tolerability, pharmacokinetics and pharmacodynamics--results from single oral dose studies in healthy volunteers. Br J Clin Pharmacol 2013; 75:1240 - 54; http://dx.doi.org/10.1111/j.1365-2125.2012.04471.x; PMID: 23013236
  • Brixen K, Chapurlat R, Cheung AM, Keaveny TM, Fuerst T, Engelke K, Recker R, Dardzinski B, Verbruggen N, Ather S, et al. Bone density, turnover, and estimated strength in postmenopausal women treated with odanacatib: a randomized trial. J Clin Endocrinol Metab 2013; 98:571 - 80; http://dx.doi.org/10.1210/jc.2012-2972; PMID: 23337728
  • Engelke K, Nagase S, Fuerst T, Small M, Kuwayama T, Deacon S, Eastell R, Genant H-K. The effect of the cathepsin K inhibitor ONO-5334 on trabecular and cortical bone in postmenopausal osteoporosis: The OCEAN study. J Bone Miner Res 2014; 29:629 - 38; http://dx.doi.org/10.1002/jbmr.2080; PMID: 24038152
  • Eastell R, Nagase S, Small M, Boonen S, Spector T, Ohyama M, Kuwayama T, Deacon S. Effect of ONO-5334 on bone mineral density and biochemical markers of bone turnover in postmenopausal osteoporosis: 2-year results from the OCEAN study. J Bone Miner Res 2014; 29:458 - 66; http://dx.doi.org/10.1002/jbmr.2047; PMID: 23873670

Reprints and Corporate Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

To request a reprint or corporate permissions for this article, please click on the relevant link below:

Academic Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

Obtain permissions instantly via Rightslink by clicking on the button below:

If you are unable to obtain permissions via Rightslink, please complete and submit this Permissions form. For more information, please visit our Permissions help page.