The regulation of osteoclast function and bone resorption by small GTPases

Small GTPases

Volumn 2, Issue 3, 2011, Pages 117-130

  Itzstein, Cecile ^a   Coxon, Fraser P ^a   Rogers, Michael J ^a  

^a UNIVERSITY OF ABERDEEN   (United Kingdom)

Author keywords

Arf; Bisphosphonate; Bone; Osteoclast; Prenylation; Rab; Rac; Ras; Rho

Indexed keywords

ADENOSINE DIPHOSPHATE RIBOSYLATION FACTOR 6; BISPHOSPHONIC ACID DERIVATIVE; F ACTIN; GUANOSINE TRIPHOSPHATASE; PROTEIN CDC42; PROTEINASE; PROTON; RAB PROTEIN; RAB7 PROTEIN; RAC PROTEIN; RHO GUANINE NUCLEOTIDE BINDING PROTEIN; RHOA GUANINE NUCLEOTIDE BINDING PROTEIN; RHOU GUANINE NUCLEOTIDE BINDING PROTEIN; UNCLASSIFIED DRUG;

APOPTOSIS; ARTICLE; BONE DEFECT; BONE DEMINERALIZATION; BONE DISEASE; CELL ACTIVITY; CELL ADHESION; CELL FUNCTION; CELL MEMBRANE; CELL MIGRATION; CELL SURVIVAL; CYTOSKELETON; DRUG MECHANISM; ENZYME ACTIVITY; ENZYME LOCALIZATION; HUMAN; OSTEOCLAST; OSTEOLYSIS; OSTEOPOROSIS; POLARIZATION; POSTMENOPAUSE OSTEOPOROSIS; PRENYLATION; PROTEIN EXPRESSION; REGULATORY MECHANISM;

EID: 79958852901     PISSN: 21541248     EISSN: 21541256     Source Type: Journal    
DOI: 10.4161/sgtp.2.3.16453     Document Type: Article

References (147)

1. Boyle WJ, Simonet WS, Lacey DL. Osteoclast differentiation and activation. Nature 2003; 423:337-42; PMID: 12748652; DOI: 10.1038/nature01658.
2. Negishi-Koga T, Takayanagi H. Ca2+-NFATc1 signaling is an essential axis of osteoclast differentiation. Immunol Rev 2009; 231:241-56; PMID: 19754901; DOI: 10.1111/j.1600-065X.2009.00821.x.
3. Teitelbaum SL. Bone resorption by osteoclasts. Science 2000; 289:1504-8; PMID: 10968780.
4. Vaananen HK, Zhao H, Mulari M, Halleen JM. The cell biology of osteoclast function. J Cell Sci 2000; 113:377-81; PMID: 10639325.
5. Spinardi L, Marchisio PC. Podosomes as smart regulators of cellular adhesion. Eur J Cell Biol 2006; 85:191-4; PMID: 16546561; DOI: 10.1016/j. ejcb.2005.08.005.
6. 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; PMID: 16546562; DOI: 10.1016/j.ejcb.2005.09.008.
7. Destaing O, Saltel F, Geminard JC, 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; PMID: 12589043; DOI: 10.1091/mbc.E02-07-0389.
8. Block MR, Badowski C, Millon-Fremillon A, Bouvard D, Bouin AP, Faurobert E, et al. Podosome-type adhesions and focal adhesions, so alike yet so different. Eur J Cell Biol 2008; 87:491-506; PMID: 18417250; DOI: 10.1016/j.ejcb.2008.02.012.
9. Luxenburg C, Geblinger D, Klein E, Anderson K, Hanein D, Geiger B, et al. The architecture of the adhesive apparatus of cultured osteoclasts: From podosome formation to sealing zone assembly. PLoS One 2007; 2:179; PMID: 17264882; DOI: 10.1371/journal. pone.0000179.
10. Mulari M, Vaaraniemi J, Vaananen HK. Intracellular membrane trafficking in bone resorbing osteoclasts. Microsc Res Tech 2003; 61:496-503; PMID: 12879417; DOI: 10.1002/jemt.10371.
11. Lakkakorpi PT, Vaananen HK. Cytoskeletal changes in osteoclasts during the resorption cycle. Microsc Res Tech 1996; 33:171-81; PMID: 8845516; DOI: 2-W.
12. Palokangas H, Mulari M, Vaananen HK. Endocytic pathway from the basal plasma membrane to the ruffled border membrane in bone-resorbing osteoclasts. J Cell Sci 1997; 110:1767-80; PMID: 9264464.
13. Zhang FL, Casey PJ. Protein prenylation: Molecular mechanisms and functional consequences. Annu Rev Biochem 1996; 65:241-69; PMID: 8811180; DOI: 10.1146/annurev.bi.65.070196.001325.
14. 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; PMID: 9556058; DOI: 10.1359/jbmr.1998.13.4.581.
15. Fisher JE, Rogers MJ, Halasy JM, Luckman SP, Hughes DE, Masarachia PJ, et al. Alendronate mechanism of action: Geranylgeraniol, an intermediate in the mevalonate pathway, prevents inhibition of osteoclast formation, bone resorption and kinase activation in vitro. Proc Natl Acad Sci USA 1999; 96:133-8; PMID: 9874784.
16. Russell RG, Watts NB, Ebetino FH, Rogers MJ. Mechanisms of action of bisphosphonates: Similarities and differences and their potential influence on clinical efficacy. Osteoporos Int 2008; 19:733-59; PMID: 18214569; DOI: 10.1007/s00198-007-0540-8.
17. Coxon FP, Thompson K, Roelofs AJ, Ebetino FH, Rogers MJ. Visualizing mineral binding and uptake of bisphosphonate by osteoclasts and non-resorbing cells. Bone 2008; 42:848-60; PMID: 18325866; DOI: 10.1016/j.bone.2007.12.225.
18. Rogers MJ, Crockett JC, Coxon FP, Monkkonen J. Biochemical and molecular mechanisms of action of bisphosphonates. Bone 2010; PMID: 21111853; DOI: 10.1016/j.bone.2010.11.008.
19. van Beek E, Pieterman E, Cohen L, Lowik C, Papapoulos S. Farnesyl pyrophosphate synthase is the molecular target of nitrogen-containing bisphosphonates. Biochem Biophys Res Commun 1999; 264:108-11; PMID: 10527849; DOI: 10.1006/bbrc.1999.1499.
20. Dunford JE, Thompson K, Coxon FP, Luckman SP, Hahn FM, Poulter CD, et al. Structure-activity relationships for inhibition of farnesyl diphosphate synthase in vitro and inhibition of bone resorption in vivo by nitrogen-containing bisphosphonates. J Pharmacol Exp Ther 2001; 296:235-42; PMID: 11160603.
21. Rogers MJ. New insights into the molecular mechanisms of action of bisphosphonates. Curr Pharm Des 2003; 9:2643-58; PMID: 14529538.
22. Kavanagh KL, Guo K, Dunford JE, Wu X, Knapp S, Ebetino FH, et al. The molecular mechanism of nitrogen-containing bisphosphonates as antiosteoporosis drugs. Proc Natl Acad Sci USA 2006; 103:7829-34; PMID: 16684881; DOI: 10.1073/pnas.0601643103.
23. Rondeau JM, Bitsch F, Bourgier E, Geiser M, Hemmig R, Kroemer M, et al. Structural basis for the exceptional in vivo efficacy of bisphosphonate drugs. ChemMedChem 2006; 1:267-73; PMID: 16892359; DOI: 10.1002/cmdc.200500059.
24. Dunford JE, Kwaasi AA, Rogers MJ, Barnett BL, Ebetino FH, Russell RG, et al. Structure-activity relationships among the nitrogen containing bisphosphonates in clinical use and other analogues: Timedependent inhibition of human farnesyl pyrophosphate synthase. J Med Chem 2008; 51:2187-95; PMID: 18327899; DOI: 10.1021/jm7015733.
25. Coxon FP, Ebetino FH, Mules EH, Seabra MC, McKenna CE, Rogers MJ. Phosphonocarboxylate inhibitors of rab geranylgeranyl transferase disrupt the prenylation and membrane localization of rab proteins in osteoclasts in vitro and in vivo. Bone 2005; 37:349-58; PMID: 16006204; DOI: 10.1016/j. bone.2005.04.021.
26. 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 structureactivity relationships in J774 macrophages. J Bone Miner Res 1998; 13:1668-78; PMID: 9797474; DOI: 10.1359/jbmr.1998.13.11.1668.
27. Roelofs AJ, Thompson K, Gordon S, Rogers MJ. Molecular mechanisms of action of bisphosphonates: Current status. Clin Cancer Res 2006; 12:6222-30; PMID: 17062705; DOI: 10.1158/1078-0432.CCR-06-0843.
28. 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; PMID: 16734383; DOI: 10.1359/jbmr.060118.
29. van beek E, Lowik C, van der Pluijm G, Papapoulos S. The role of geranylgeranylation in bone resorption and its suppression by bisphosphonates in fetal bone explants in vitro: A clue to the mechanism of action of nitrogen-containing bisphosphonates. J Bone Miner Res 1999; 14:722-9; PMID: 10320520; DOI: 10.1359/jbmr.1999.14.5.722.
30. Coxon FP, Helfrich MH, Van't Hof R, Sebti S, Ralston SH, Hamilton A, et al. Protein geranylgeranylation is required for osteoclast formation, function and survival: Inhibition by bisphosphonates and GGTI-298. J Bone Miner Res 2000; 15:1467-76; PMID: 10934645; DOI: 10.1359/jbmr.2000.15.8.1467.
31. Coxon FP, Helfrich MH, Larijani B, Muzylak M, Dunford JE, Marshall D, et al. Identification of a novel phosphonocarboxylate inhibitor of rab geranylgeranyl transferase that specifically prevents rab prenylation in osteoclasts and macrophages. J Biol Chem 2001; 276:48213-22; PMID: 11581260; DOI: 10.1074/jbc. M106473200.
32. Baron RA, Tavare R, Figueiredo AC, Blazewska KM, Kashemirov BA, McKenna CE, et al. Phosphonocarboxylates inhibit the second geranylgeranyl addition by rab geranylgeranyl transferase. J Biol Chem 2009; 284:6861-8; PMID: 19074143; DOI: 10.1074/jbc.M806952200.
33. Detter JC, Zhang Q, Mules EH, Novak EK, Mishra VS, Li W, et al. Rab geranylgeranyl transferase alpha mutation in the gunmetal mouse reduces rab prenylation and platelet synthesis. Proc Natl Acad Sci USA 2000; 97:4144-9; PMID: 10737774; DOI: 10.1073/pnas.080517697.
34. Coxon FP, Taylor A, Stewart CA, Baron R, Seabra MC, Ebetino FH, et al. The gunmetal mouse reveals rab geranylgeranyl transferase to be the major molecular target of phosphonocarboxylate analogues of bisphosphonates. Bone 2011; PMID: 21419243; DOI: 10.1016/j.bone.2011.03.686.
35. Taylor A, Mules EH, Seabra MC, Rogers MJ, Coxon FP. Impaired prenylation of Rab GTPases in the gunmetal mouse causes defects in bone cell function. Small GTPases 2011; In press.
36. Nakamura I, Pilkington MF, Lakkakorpi PT, Lipfert L, Sims SM, Dixon SJ, et al. Role of alpha(v)beta(3) integrin in osteoclast migration and formation of the sealing zone. J Cell Sci 1999; 112:3985-93; PMID: 10547359.
37. McHugh KP, Hodivala-Dilke K, Zheng MH, Namba N, Lam J, Novack D, et al. Mice lacking beta3 integrins are osteosclerotic because of dysfunctional osteoclasts. J Clin Invest 2000; 105:433-40; PMID: 10683372; DOI: 10.1172/JCI8905.
38. Clover J, Dodds RA, Gowen M. Integrin subunit expression by human osteoblasts and osteoclasts in situ and in culture. J Cell Sci 1992; 103:267-71; PMID: 1429908.
39. Shinar DM, Schmidt A, Halperin D, Rodan GA, Weinreb M. Expression of alphav and beta3 integrin subunits in rat osteoclasts in situ. J Bone Miner Res 1993; 8:403-14; PMID: 8475790; DOI: 10.1002/jbmr.5650080404.
40. Duong LT, Lakkakorpi PT, Nakamura I, Machwate M, Nagy RM, Rodan GA. PYK2 in osteoclasts is an adhesion kinase, localized in the sealing zone, activated by ligation of alpha(v)beta3 integrin and phosphorylated by src kinase. J Clin Invest 1998; 102:881-92; PMID: 9727056; DOI: 10.1172/JCI3212.
41. Sanjay A, Houghton A, Neff L, DiDomenico E, Bardelay C, Antoine E, et al. Cbl associates with Pyk2 and src to regulate src kinase activity, alpha(v)beta(3) integrin-mediated signaling, cell adhesion and osteoclast motility. J Cell Biol 2001; 152:181-95; PMID: 11149930.
42. Zou W, Kitaura H, Reeve J, Long F, Tybulewicz VL, Shattil SJ, et al. Syk, c-src, the alphavbeta3 integrin and ITAM immunoreceptors, in concert, regulate osteoclastic bone resorption. J Cell Biol 2007; 176:877-88; PMID: 17353363; DOI: 10.1083/jcb.200611083.
43. Miyazaki T, Sanjay A, Neff L, Tanaka S, Horne WC, Baron R. Src kinase activity is essential for osteoclast function. J Biol Chem 2004; 279:17660-6; PMID: 14739300; DOI: 10.1074/jbc.M311032200.
44. Gil-Henn H, Destaing O, Sims NA, Aoki K, Alles N, Neff L, et al. Defective microtubule-dependent podosome organization in osteoclasts leads to increased bone density in Pyk2(-/-) mice. J Cell Biol 2007; 178:1053-64; PMID: 17846174; DOI: 10.1083/jcb.200701148.
45. Chiusaroli R, Sanjay A, Henriksen K, Engsig MT, Horne WC, Gu H, et al. Deletion of the gene encoding c-cbl alters the ability of osteoclasts to migrate, delaying resorption and ossification of cartilage during the development of long bones. Dev Biol 2003; 261:537-47; PMID: 14499658.
46. Destaing O, Sanjay A, Itzstein C, Horne WC, Toomre D, De Camilli P, et al. The tyrosine kinase activity of c-src regulates actin dynamics and organization of podosomes in osteoclasts. Mol Biol Cell 2008; 19:394-404; PMID: 17978100; DOI: 10.1091/mbc.E07-03-0227.
47. 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; PMID: 16939397; DOI: 10.1359/jbmr.060613.
48. Ory S, Brazier H, Pawlak G, Blangy A. Rho GTPases in osteoclasts: Orchestrators of podosome arrangement. Eur J Cell Biol 2008; 87:469-77; PMID: 18436334; DOI: 10.1016/j.ejcb.2008.03.002.
49. Myers KR, Casanova JE. Regulation of actin cytoskeleton dynamics by arf-family GTPases. Trends Cell Biol 2008; 18:184-92; PMID: 18328709; DOI: 10.1016/j. tcb.2008.02.002.
50. Heckel T, Czupalla C, Expirto Santo AI, Anitei M, Arantzazu Sanchez-Fernandez M, Mosch K, et al. Srcdependent repression of ARF6 is required to maintain podosome-rich sealing zones in bone-digesting osteoclasts. Proc Natl Acad Sci USA 2009; 106:1451-6; PMID: 19164586; DOI: 10.1073/pnas.0804464106.
51. Zhang D, Udagawa N, Nakamura I, Murakami H, Saito S, Yamasaki K, 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.
52. Saltel F, Destaing O, Bard F, Eichert D, Jurdic P. Apatite-mediated actin dynamics in resorbing osteoclasts. Mol Biol Cell 2004; 15:5231-41; PMID: 15371537; DOI: 10.1091/mbc.E04-06-0522.
53. Whyte LS, Ryberg E, Sims NA, Ridge SA, Mackie K, Greasley PJ, et al. The putative cannabinoid receptor GPR55 affects osteoclast function in vitro and bone mass in vivo. Proc Natl Acad Sci USA 2009; 106:16511-6; PMID: 19805329; DOI: 10.1073/pnas.0902743106.
54. 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.
55. Chellaiah MA, Soga N, Swanson S, McAllister S, Alvarez U, Wang D, et al. Rho-A is critical for osteoclast podosome organization, motility and bone resorption. J Biol Chem 2000; 275:11993-2002; PMID: 10766830.
56. Destaing O, Saltel F, Gilquin B, Chabadel A, Khochbin S, Ory S, et al. A novel rho-mDia2-HDAC6 pathway controls podosome patterning through microtubule acetylation in osteoclasts. J Cell Sci 2005; 118:2901-11; PMID: 15976449; DOI: 10.1242/jcs.02425.
57. Chellaiah MA. Regulation of actin ring formation by rho GTPases in osteoclasts. J Biol Chem 2005; 280:32930-43; PMID: 16006560; DOI: 10.1074/jbc. M500154200.
58. Schramp M, Ying O, Kim TY, Martin GS. ERK5 promotes src-induced podosome formation by limiting rho activation. J Cell Biol 2008; 181:1195-210; PMID: 18573916; DOI: 10.1083/jcb.200801078.
59. Fukuda A, Hikita A, Wakeyama H, Akiyama T, Oda H, Nakamura K, et al. Regulation of osteoclast apoptosis and motility by small GTPase binding protein Rac1. J Bone Miner Res 2005; 20:2245-53; PMID: 16294277; DOI: 10.1359/JBMR.050816.
60. Sakai H, Chen Y, Itokawa T, Yu KP, Zhu ML, Insogna K. Activated c-fms recruits vav and rac during CSF-1-induced cytoskeletal remodeling and spreading in osteoclasts. Bone 2006; 39:1290-301; PMID: 16950670; DOI: 10.1016/j.bone.2006.06.012.
61. Razzouk S, Lieberherr M, Cournot G. Rac-GTPase, osteoclast cytoskeleton and bone resorption. Eur J Cell Biol 1999; 78:249-55; PMID: 10350213.
62. Itokowa T, Zhu ML, Troiano N, Bian J, Kawano T, Insogna K. Osteoclasts lacking Rac2 have defective chemotaxis and resorptive activity. Calcif Tissue Int 2010; PMID: 21110188; DOI: 10.1007/s00223-010-9435-3.
63. Rossman KL, Der CJ, Sondek J. GEF means go: Turning on RHO GTPases with guanine nucleotideexchange factors. Nat Rev Mol Cell Biol 2005; 6:167-80; PMID: 15688002; DOI: 10.1038/nrm1587.
64. Meller N, Merlot S, Guda C. CZH proteins: A new family of rho-GEFs. J Cell Sci 2005; 118:4937-46; PMID: 16254241; DOI: 10.1242/jcs.02671.
65. Faccio R, Teitelbaum SL, Fujikawa K, Chappel J, Zallone A, Tybulewicz VL, et al. Vav3 regulates osteoclast function and bone mass. Nat Med 2005; 11:284-90; PMID: 15711558; DOI: 10.1038/nm1194.
66. Kubo T, Yamashita T, Yamaguchi A, Sumimoto H, Hosokawa K, Tohyama M. A novel FERM domain including guanine nucleotide exchange factor is involved in rac signaling and regulates neurite remodeling. J Neurosci 2002; 22:8504-13; PMID: 12351724.
67. Takegahara N, Kang S, Nojima S, Takamatsu H, Okuno T, Kikutani H, et al. Integral roles of a guanine nucleotide exchange factor, FARP2, in osteoclast podosome rearrangements. FASEB J 2010; 24:4782-92; PMID: 20702777; DOI: 10.1096/fj.10-158212.
68. Vives V, Laurin M, Cres G, Larrousse P, Morichaud Z, Noel D, et al. The Rac1 exchange factor Dock5 is essential for bone resorption by osteoclasts. J Bone Miner Res 2010; PMID: 21053312; DOI: 10.1002/jbmr.282.
69. Radhakrishna H, Al-Awar O, Khachikian Z, Donaldson JG. ARF6 requirement for rac ruffling suggests a role for membrane trafficking in cortical actin rearrangements. J Cell Sci 1999; 112:855-66; PMID: 10036235.
70. Tushir JS, D'Souza-Schorey C. ARF6-dependent activation of ERK and Rac1 modulates epithelial tubule development. EMBO J 2007; 26:1806-19; PMID: 17363898; DOI: 10.1038/sj.emboj.7601644.
71. Menon P, Yin G, Smolock EM, Zuscik MJ, Yan C, Berk BC. GPCR kinase 2 interacting protein 1 (GIT1) regulates osteoclast function and bone mass. J Cell Physiol 2010; 225:777-85; PMID: 20568227; DOI: 10.1002/jcp.22282.
72. Gringel A, Walz D, Rosenberger G, Minden A, Kutsche K, Kopp P, et al. PAK4 and alphaPIX determine podosome size and number in macrophages through localized actin regulation. J Cell Physiol 2006; 209:568-79; PMID: 16897755; DOI: 10.1002/jcp.20777.
73. Frank SR, Hansen SH. The PIX-GIT complex: A G protein signaling cassette in control of cell shape. Semin Cell Dev Biol 2008; 19:234-44; PMID: 18299239; DOI: 10.1016/j.semcdb.2008.01.002.
74. Rosenberger G, Kutsche K. AlphaPIX and betaPIX and their role in focal adhesion formation. Eur J Cell Biol 2006; 85:265-74; PMID: 16337026; DOI: 10.1016/j. ejcb.2005.10.007.
75. Webb BA, Eves R, Crawley SW, Zhou S, Cote GP, Mak AS. PAK1 induces podosome formation in A7r5 vascular smooth muscle cells in a PAK-interacting exchange factor-dependent manner. Am J Physiol Cell Physiol 2005; 289:898-907; PMID: 15944209; DOI: 10.1152/ajpcell.00095.2005.
76. Rohatgi R, Ma L, Miki H, Lopez M, Kirchhausen T, Takenawa T, et al. The interaction between N-WASP and the Arp2/3 complex links Cdc42-dependent signals to actin assembly. Cell 1999; 97:221-31; PMID: 10219243.
77. Monypenny J, Chou HC, Banon-Rodriguez I, Thrasher AJ, Anton IM, Jones GE, et al. Role of WASP in cell polarity and podosome dynamics of myeloid cells. Eur J Cell Biol 2010; PMID: 20609498; DOI: 10.1016/j. ejcb.2010.05.009.
78. Joberty G, Petersen C, Gao L, Macara IG. The cellpolarity protein Par6 links Par3 and atypical protein kinase C to Cdc42. Nat Cell Biol 2000; 2:531-9; PMID: 10934474; DOI: 10.1038/35019573.
79. Ito Y, Teitelbaum SL, Zou W, Zheng Y, Johnson JF, Chappel J, et al. Cdc42 regulates bone modeling and remodeling in mice by modulating RANKL/MCSF signaling and osteoclast polarization. J Clin Invest 2010; 120:1981-93; PMID: 20501942; DOI: 10.1172/JCI39650; 10.1172/JCI39650.
80. Calle Y, Jones GE, Jagger C, Fuller K, Blundell MP, Chow J, et al. WASp deficiency in mice results in failure to form osteoclast sealing zones and defects in bone resorption. Blood 2004; 103:3552-61; PMID: 14726392; DOI: 10.1182/blood-2003-04-1259.
81. Chellaiah MA, Kuppuswamy D, Lasky L, Linder S. Phosphorylation of a wiscott-aldrich syndrome proteinassociated signal complex is critical in osteoclast bone resorption. J Biol Chem 2007; 282:10104-16; PMID: 17283076; DOI: 10.1074/jbc.M608957200.
82. 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; PMID: 18289379; DOI: 10.1186/1750-2187-3-4.
83. Chou HC, Anton IM, Holt MR, Curcio C, Lanzardo S, Worth A, et al. WIP regulates the stability and localization of WASP to podosomes in migrating dendritic cells. Curr Biol 2006; 16:2337-44; PMID: 17141616; DOI: 10.1016/j.cub.2006.10.037.
84. Chabadel A, Banon-Rodriguez I, Cluet D, Rudkin BB, Wehrle-Haller B, Genot E, et al. CD44 and beta3 integrin organize two functionally distinct actin-based domains in osteoclasts. Mol Biol Cell 2007; 18:4899-910; PMID: 17898081; DOI: 10.1091/mbc.E07-04-0378.
85. Szczepanowska J. Involvement of Rac/Cdc42/PAK pathway in cytoskeletal rearrangements. Acta Biochim Pol 2009; 56:225-34; PMID: 19513348.
86. Webb BA, Eves R, Mak AS. Cortactin regulates podosome formation: Roles of the protein interaction domains. Exp Cell Res 2006; 312:760-9; PMID: 16434035; DOI: 10.1016/j.yexcr.2005.11.032.
87. Luxenburg C, Parsons JT, Addadi L, Geiger B. Involvement of the src-cortactin pathway in podosome formation and turnover during polarization of cultured osteoclasts. J Cell Sci 2006; 119:4878-88; PMID: 17105771; DOI: 10.1242/jcs.03271.
88. Webb BA, Zhou S, Eves R, Shen L, Jia L, Mak AS. Phosphorylation of cortactin by p21-activated kinase. Arch Biochem Biophys 2006; 456:183-93; PMID: 16854367; DOI: 10.1016/j.abb.2006.06.011.
89. Saras J, Wollberg P, Aspenstrom P. Wrch1 is a GTPasedeficient Cdc42-like protein with unusual binding characteristics and cellular effects. Exp Cell Res 2004; 299:356-69; PMID: 15350535; DOI: 10.1016/j. yexcr.2004.05.029.
90. Ory S, Brazier H, Blangy A. Identification of a bipartite focal adhesion localization signal in RhoU/Wrch-1, a rho family GTPase that regulates cell adhesion and migration. Biol Cell 2007; 99:701-16; PMID: 17620058; DOI: 10.1042/BC20070058.
91. Brady DC, Alan JK, Madigan JP, Fanning AS, Cox AD. The transforming rho family GTPase wrch-1 disrupts epithelial cell tight junctions and epithelial morphogenesis. Mol Cell Biol 2009; 29:1035-49; PMID: 19064640; DOI: 10.1128/MCB.00336-08.
92. Alan JK, Berzat AC, Dewar BJ, Graves LM, Cox AD. Regulation of the rho family small GTPase wrch-1/RhoU by C-terminal tyrosine phosphorylation requires src. Mol Cell Biol 2010; 30:4324-38; PMID: 20547754; DOI: 10.1128/MCB.01646-09.
93. 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; PMID: 19135548; DOI: 10.1016/j. biocel.2008.12.007.
94. Salo J, Metsikko K, Palokangas H, Lehenkari P, Vaananen HK. Bone-resorbing osteoclasts reveal a dynamic division of basal plasma membrane into two different domains. J Cell Sci 1996; 109:301-7; PMID: 8838653.
95. Zhao H, Ettala O, Vaananen HK. Intracellular membrane trafficking pathways in bone-resorbing osteoclasts revealed by cloning and subcellular localization studies of small GTP-binding rab proteins. Biochem Biophys Res Commun 2002; 293:1060-5; PMID: 12051767; DOI: 10.1016/S0006-291X(02)00326-1.
96. Blair HC, Teitelbaum SL, Ghiselli R, Gluck S. Osteoclastic bone resorption by a polarized vacuolar proton pump. Science 1989; 245:855-7; PMID: 2528207.
97. Toyomura T, Murata Y, Yamamoto A, Oka T, Sun-Wada GH, Wada Y, et al. From lysosomes to the plasma membrane: Localization of vacuolar-type H+-ATPase with the a3 isoform during osteoclast differentiation. J Biol Chem 2003; 278:22023-30; PMID: 12672822; DOI: 10.1074/jbc.M302436200.
98. Kornak U, Kasper D, Bosl MR, Kaiser E, Schweizer M, Schulz A, et al. Loss of the ClC-7 chloride channel leads to osteopetrosis in mice and man. Cell 2001; 104:205-15; PMID: 11207362.
99. Zhao H, Vaananen HK. Pharmacological sequestration of intracellular cholesterol in late endosomes disrupts ruffled border formation in osteoclasts. J Bone Miner Res 2006; 21:456-65; PMID: 16491294; DOI: 10.1359/JBMR.051204.
100. Zaidi M, Troen B, Moonga BS, Abe E. Cathepsin K, osteoclastic resorption and osteoporosis therapy. J Bone Miner Res 2001; 16:1747-9; PMID: 11585336; DOI: 10.1359/jbmr.2001.16.10.1747.
101. Everts V, Delaisse JM, Korper W, Niehof A, Vaes G, Beertsen W. Degradation of collagen in the boneresorbing compartment underlying the osteoclast involves both cysteine-proteinases and matrix metalloproteinases. J Cell Physiol 1992; 150:221-31; PMID: 1734028; DOI: 10.1002/jcp.1041500202.
102. Mulari MT, Zhao H, Lakkakorpi PT, Vaananen HK. Osteoclast ruffled border has distinct subdomains for secretion and degraded matrix uptake. Traffic 2003; 4:113-25; PMID: 12559037.
103. Schwartz SL, Cao C, Pylypenko O, Rak A, Wandinger-Ness A. Rab GTPases at a glance. J Cell Sci 2007; 120:3905-10; PMID: 17989088; DOI: 10.1242/jcs.015909.
104. Zacchi P, Stenmark H, Parton RG, Orioli D, Lim F, Giner A, et al. Rab17 regulates membrane trafficking through apical recycling endosomes in polarized epithelial cells. J Cell Biol 1998; 140:1039-53; PMID: 9490718.
105. Kariya Y, Honma M, Hanamura A, Aoki S, Ninomiya T, Nakamichi Y, et al. Rab27a and Rab27b are involved in stimulation-dependent RANKL release from secretory lysosomes in osteoblastic cells. J Bone Miner Res 2010; PMID: 20939018; DOI: 10.1002/jbmr.268.
106. Ha BG, Hong JM, Park JY, Ha MH, Kim TH, Cho JY, et al. Proteomic profile of osteoclast membrane proteins: Identification of Na+/H+ exchanger domain containing 2 and its role in osteoclast fusion. Proteomics 2008; 8:2625-39; PMID: 18600791; DOI: 10.1002/pmic.200701192.
107. Pavlos NJ, Xu J, Riedel D, Yeoh JS, Teitelbaum SL, Papadimitriou JM, et al. Rab3D regulates a novel vesicular trafficking pathway that is required for osteoclastic bone resorption. Mol Cell Biol 2005; 25:5253-69; PMID: 15923639; DOI: 10.1128/MCB.25.12.5253-69.2005.
108. Taylor A, Rogers MJ, Tosh D, Coxon FP. A novel method for efficient generation of transfected human osteoclasts. Calcif Tissue Int 2007; 80:132-6; PMID: 17308995; DOI: 10.1007/s00223-006-0245-6.
109. Feng Y, Press B, Wandinger-Ness A. Rab 7: An important regulator of late endocytic membrane traffic. J Cell Biol 1995; 131:1435-52; PMID: 8522602.
110. Bucci C, Thomsen P, Nicoziani P, McCarthy J, van Deurs B. Rab7: A key to lysosome biogenesis. Mol Biol Cell 2000; 11:467-80; PMID: 10679007.
111. Jordens I, Fernandez-Borja M, Marsman M, Dusseljee S, Janssen L, Calafat J, et al. The Rab7 effector protein RILP controls lysosomal transport by inducing the recruitment of dynein-dynactin motors. Curr Biol 2001; 11:1680-5; PMID: 11696325.
112. Zhao H, Laitala-Leinonen T, Parikka V, Vaananen HK. Downregulation of small GTPase Rab7 impairs osteoclast polarization and bone resorption. J Biol Chem 2001; 276:39295-302; PMID: 11514537; DOI: 10.1074/jbc.M010999200.
113. Sun Y, Buki KG, Ettala O, Vaaraniemi JP, Vaananen HK. Possible role of direct Rac1-Rab7 interaction in ruffled border formation of osteoclasts. J Biol Chem 2005; 280:32356-61; PMID: 16040606; DOI: 10.1074/jbc.M414213200.
114. Hume AN, Ushakov DS, Tarafder AK, Ferenczi MA, Seabra MC. Rab27a and MyoVa are the primary mlph interactors regulating melanosome transport in melanocytes. J Cell Sci 2007; 120:3111-22; PMID: 17698919; DOI: 10.1242/jcs.010207.
115. Frasa MA, Maximiano FC, Smolarczyk K, Francis RE, Betson ME, Lozano E, et al. Armus is a Rac1 effector that inactivates Rab7 and regulates E-cadherin degradation. Curr Biol 2010; 20:198-208; PMID: 20116244; DOI: 10.1016/j.cub.2009.12.053.
116. Nakamura I, Takahashi N, Udagawa N, Moriyama Y, Kurokawa T, Jimi E, et al. Lack of vacuolar proton ATPase association with the cytoskeleton in osteoclasts of osteosclerotic (oc/oc) mice. FEBS Lett 1997; 401:207-12; PMID: 9013888.
117. Zuo J, Jiang J, Chen SH, Vergara S, Gong Y, Xue J, et al. Actin binding activity of subunit B of vacuolar H+-ATPase is involved in its targeting to ruffled membranes of osteoclasts. J Bone Miner Res 2006; 21:714-21; PMID: 16734386; DOI: 10.1359/jbmr.060201.
118. Van Wesenbeeck L, Odgren PR, Coxon FP, Frattini A, Moens P, Perdu B, et al. Involvement of PLEKHM1 in osteoclastic vesicular transport and osteopetrosis in incisors absent rats and humans. J Clin Invest 2007; 117:919-30; PMID: 17404618; DOI: 10.1172/JCI30328.
119. Tabata K, Matsunaga K, Sakane A, Sasaki T, Noda T, Yoshimori T. Rubicon and PLEKHM1 negatively regulate the endocytic/autophagic pathway via a novel Rab7-binding domain. Mol Biol Cell 2010; 21:4162-72; PMID: 20943950; DOI: 10.1091/mbc.E10-06-0495.
120. Del Fattore A, Fornari R, Van Wesenbeeck L, de Freitas F, Timmermans JP, Peruzzi B, et al. A new heterozygous mutation (R714C) of the osteopetrosis gene, pleckstrin homolog domain containing family M (with run domain) member 1 (PLEKHM1), impairs vesicular acidification and increases TRACP secretion in osteoclasts. J Bone Miner Res 2008; 23:380-91; PMID: 17997709; DOI: 10.1359/jbmr.071107.
121. Jager S, Bucci C, Tanida I, Ueno T, Kominami E, Saftig P, et al. Role for Rab7 in maturation of late autophagic vacuoles. J Cell Sci 2004; 117:4837-48; PMID: 15340014; DOI: 10.1242/jcs.01370.
122. Pankiv S, Alemu EA, Brech A, Bruun JA, Lamark T, Overvatn A, et al. FYCO1 is a Rab7 effector that binds to LC3 and PI3P to mediate microtubule plus enddirected vesicle transport. J Cell Biol 2010; 188:253-69; PMID: 20100911; DOI: 10.1083/jcb.200907015.
123. Bjorkoy G, Lamark T, Brech A, Outzen H, Perander M, Overvatn A, et al. p62/SQSTM1 forms protein aggregates degraded by autophagy and has a protective effect on huntingtin-induced cell death. J Cell Biol 2005; 171:603-14; PMID: 16286508; DOI: 10.1083/jcb.200507002.
124. Noda T, Fujita N, Yoshimori T. The late stages of autophagy: How does the end begin? Cell Death Differ 2009; 16:984-90; PMID: 19424283; DOI: 10.1038/cdd.2009.54.
125. Sanjuan MA, Dillon CP, Tait SW, Moshiach S, Dorsey F, Connell S, et al. Toll-like receptor signalling in macrophages links the autophagy pathway to phagocytosis. Nature 2007; 450:1253-7; PMID: 18097414; DOI: 10.1038/nature06421.
126. Lledo PM, Johannes L, Vernier P, Zorec R, Darchen F, Vincent JD, et al. Rab3 proteins: Key players in the control of exocytosis. Trends Neurosci 1994; 17:426-32; PMID: 7530881.
127. Millar AL, Pavios NJ, Xu J, Zheng MH. Rab3D: A regulator of exocytosis in non-neuronal cells. Histol Histopathol 2002; 17:929-36; PMID: 12168804.
128. Pavlos NJ, Xu J, Feng H, Ng P, Cheng T, Ang E, et al. Rab3D directs organelle transport by recruiting cytoplasmic dynein motor protein tctex-1 to secretory membranes of osteoclast. Bone 2009; 44:160; DOI: DOI: 10.1016/j.bone.2009.01.354.
129. Stenbeck G, Horton MA. A new specialized cell-matrix interaction in actively resorbing osteoclasts. J Cell Sci 2000; 113:1577-87; PMID: 10751149.
130. Salo J, Lehenkari P, Mulari M, Metsikko K, Vaananen HK. Removal of osteoclast bone resorption products by transcytosis. Science 1997; 276:270-3; PMID: 9092479.
131. Nesbitt SA, Horton MA. Trafficking of matrix collagens through bone-resorbing osteoclasts. Science 1997; 276:266-9; PMID: 9092478.
132. Vaaraniemi J, Halleen JM, Kaarlonen K, Ylipahkala H, Alatalo SL, Andersson G, et al. Intracellular machinery for matrix degradation in bone-resorbing osteoclasts. J Bone Miner Res 2004; 19:1432-40; PMID: 15312243; DOI: 10.1359/JBMR.040603.
133. Stenbeck G, Horton MA. Endocytic trafficking in actively resorbing osteoclasts. J Cell Sci 2004; 117:827-36; PMID: 14762112; DOI: 10.1242/jcs.00935.
134. Mulari MT, Nars M, Laitala-Leinonen T, Kaisto T, Metsikko K, Sun Y, et al. Recombinant VSV G proteins reveal a novel raft-dependent endocytic pathway in resorbing osteoclasts. Exp Cell Res 2008; 314:1641-51; PMID: 18387607; DOI: 10.1016/j. yexcr.2008.02.011.
135. Hunziker W, Peters PJ. Rab17 localizes to recycling endosomes and regulates receptor-mediated transcytosis in epithelial cells. J Biol Chem 1998; 273:15734-41; PMID: 9624171.
136. Su T, Bryant DM, Luton F, Verges M, Ulrich SM, Hansen KC, et al. A kinase cascade leading to Rab11-FIP5 controls transcytosis of the polymeric immunoglobulin receptor. Nat Cell Biol 2010; 12:1143-53; PMID: 21037565; DOI: 10.1038/ncb2118.
137. Benford HL, McGowan NW, Helfrich MH, Nuttall ME, Rogers MJ. Visualization of bisphosphonateinduced caspase-3 activity in apoptotic osteoclasts in vitro. Bone 2001; 28:465-73; PMID: 11344045.
138. Fehrenbacher N, Bar-Sagi D, Philips M. Ras/MAPK signaling from endomembranes. Mol Oncol 2009; 3:297-307; PMID: 19615955; DOI: 10.1016/j. molonc.2009.06.004.
139. Vanhaesebroeck B, Alessi DR. The PI3K-PDK1 connection: More than just a road to PKB. Biochem J 2000; 346:561-76; PMID: 10698680.
140. Bradley EW, Ruan MM, Vrable A, Oursler MJ. Pathway crosstalk between Ras/Raf and PI3K in promotion of M-CSF-induced MEK/ERK-mediated osteoclast survival. J Cell Biochem 2008; 104:1439-51; PMID: 18275061; DOI: 10.1002/jcb.21719.
141. Miyazaki T, Katagiri H, Kanegae Y, Takayanagi H, Sawada Y, Yamamoto A, et al. Reciprocal role of ERK and NFkappaB pathways in survival and activation of osteoclasts. J Cell Biol 2000; 148:333-42; PMID: 10648566.
142. Bradley EW, Ruan MM, Oursler MJ. PAK1 is a novel MEK-independent raf target controlling expression of the IAP survivin in M-CSF-mediated osteoclast survival. J Cell Physiol 2008; 217:752-8; PMID: 18668521; DOI: 10.1002/jcp.21550.
143. Schindeler A, Little DG. Recent insights into bone development, homeostasis and repair in type 1 neurofibromatosis (NF1). Bone 2008; 42:616-22; PMID: 18248783; DOI: 10.1016/j.bone.2007.11.006.
144. Heerva E, Alanne MH, Peltonen S, Kuorilehto T, Hentunen T, Vaananen K, et al. Osteoclasts in neurofibromatosis type 1 display enhanced resorption capacity, aberrant morphology and resistance to serum deprivation. Bone 2010; 47:583-90; PMID: 20541045; DOI: 10.1016/j.bone.2010.06.001.
145. Pascoe D, Oursler MJ. The src signaling pathway regulates osteoclast lysosomal enzyme secretion and is rapidly modulated by estrogen. J Bone Miner Res 2001; 16:1028-36; PMID: 11393779; DOI: 10.1359/jbmr.2001.16.6.1028.
146. Yang FC, Chen S, Robling AG, Yu X, Nebesio TD, Yan J, et al. Hyperactivation of p21ras and PI3K cooperate to alter murine and human neurofibromatosis type 1-haploinsufficient osteoclast functions. J Clin Invest 2006; 116:2880-91; PMID: 17053831; DOI: 10.1172/JCI29092.
147. Yan J, Chen S, Zhang Y, Li X, Li Y, Wu X, et al. Rac1 mediates the osteoclast gains-in-function induced by haploinsufficiency of Nf1. Hum Mol Genet 2008; 17:936-48; PMID: 18089636; DOI: 10.1093/hmg/ddm366.