{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,2]],"date-time":"2026-10-02T10:00:46Z","timestamp":1790935246942,"version":"4.1.0"},"reference-count":33,"publisher":"The Company of Biologists","issue":"22","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2011,11,15]]},"abstract":"<jats:p>Cdc42 mediates bone resorption principally by stimulating osteoclastogenesis. Whether its sister GTPase, Rac, meaningfully impacts upon the osteoclast and, if so, by what means, is unclear. We find that whereas deletion of Rac1 or Rac2 alone has no effect, variable reduction of Rac1 in osteoclastic cells of Rac2\u2212\/\u2212 mice causes severe osteopetrosis. Osteoclasts lacking Rac1 and Rac2 in combination (Rac double-knockout, RacDKO), fail to effectively resorb bone. By contrast, osteoclasts are abundant in RacDKO osteopetrotic mice and, unlike those deficient in Cdc42, express the maturation markers of the cells normally. Hence, the osteopetrotic lesion of RacDKO mice largely reflects impaired function, and not arrested differentiation, of the resorptive polykaryon. The dysfunction of RacDKO osteoclasts represents failed cytoskeleton organization as evidenced by reduced motility of the cells and their inability to spread or generate the key resorptive organelles (i.e. actin rings and ruffled borders), which is accompanied by abnormal Arp3 distribution. The cytoskeleton-organizing capacity of Rac1 is mediated through its 20-amino-acid effector domain. Thus, Rac1 and Rac2 are mutually compensatory. Unlike Cdc42 deficiency, their combined absence does not impact upon differentiation but promotes severe osteopetrosis by dysregulating the osteoclast cytoskeleton.<\/jats:p>","DOI":"10.1242\/jcs.086280","type":"journal-article","created":{"date-parts":[[2011,11,24]],"date-time":"2011-11-24T03:11:06Z","timestamp":1322104266000},"page":"3811-3821","source":"Crossref","is-referenced-by-count":100,"title":["Rac deletion in osteoclasts causes severe osteopetrosis"],"prefix":"10.1242","volume":"124","author":[{"given":"Monica","family":"Croke","sequence":"first","affiliation":[{"name":"Department of Pathology and Immunology, Washington University in St. Louis, School of Medicine, St. Louis, MO 63110, USA"},{"name":"Division of Biology and Biomedical Sciences, Washington University in St. Louis, School of Medicine, St. Louis, MO 63110, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"F. Patrick","family":"Ross","sequence":"additional","affiliation":[{"name":"Department of Pathology and Immunology, Washington University in St. Louis, School of Medicine, St. Louis, MO 63110, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matti","family":"Korhonen","sequence":"additional","affiliation":[{"name":"Finnish Red Cross Blood Service, Helsinki, Finland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David A.","family":"Williams","sequence":"additional","affiliation":[{"name":"Division of Hematology\/Oncology, Children's Hospital Boston, Boston, MA 02115, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wei","family":"Zou","sequence":"additional","affiliation":[{"name":"Department of Pathology and Immunology, Washington University in St. Louis, School of Medicine, St. Louis, MO 63110, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Steven L.","family":"Teitelbaum","sequence":"additional","affiliation":[{"name":"Department of Pathology and Immunology, Washington University in St. Louis, School of Medicine, St. Louis, MO 63110, USA"},{"name":"Division of Bone and Mineral Diseases, Department of Internal Medicine, Washington University in St. Louis, School of Medicine, St. Louis, MO 63110, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"237","reference":[{"key":"2021042621083641800_R1","doi-asserted-by":"crossref","first-page":"265","DOI":"10.1023\/A:1008942828960","article-title":"Conditional gene targeting in macrophages and granulocytes using LysMcre mice","volume":"8","author":"Clausen","year":"1999","journal-title":"Transgenic Res."},{"key":"2021042621083641800_R2","doi-asserted-by":"crossref","first-page":"701","DOI":"10.1056\/NEJM198003273021301","article-title":"Successful bone-marrow transplantation for infantile malignant osteopetrosis","volume":"302","author":"Coccia","year":"1980","journal-title":"N. Engl. J. Med."},{"key":"2021042621083641800_R3","doi-asserted-by":"crossref","first-page":"232","DOI":"10.1038\/ncb759","article-title":"Integrins regulate GTP-Rac localized effector interactions through dissociation of Rho-GDI","volume":"4","author":"Del Pozo","year":"2002","journal-title":"Nat. Cell Biol."},{"key":"2021042621083641800_R4","doi-asserted-by":"crossref","first-page":"242","DOI":"10.1002\/jbmr.212","article-title":"Odanacatib in the treatment of postmenopausal women with low bone mineral density: Three-year continued therapy and resolution of effect","volume":"26","author":"Eisman","year":"2011","journal-title":"J. Bone Miner."},{"key":"2021042621083641800_R5","doi-asserted-by":"crossref","first-page":"499","DOI":"10.1083\/jcb.200212082","article-title":"Dynamic changes in the osteoclast cytoskeleton in response to growth factors and cell attachment are controlled by \u03b23 integrin","volume":"162","author":"Faccio","year":"2003","journal-title":"J. Cell Biol."},{"key":"2021042621083641800_R6","doi-asserted-by":"crossref","first-page":"749","DOI":"10.1172\/JCI200316924","article-title":"c-Fms and the \u03b1v\u03b23 integrin collaborate during osteoclast differentiation","volume":"111","author":"Faccio","year":"2003","journal-title":"J. Clin. Invest."},{"key":"2021042621083641800_R7","doi-asserted-by":"crossref","first-page":"284","DOI":"10.1038\/nm1194","article-title":"Vav3 regulates osteoclast function and bone mass","volume":"11","author":"Faccio","year":"2005","journal-title":"Nat. Med."},{"key":"2021042621083641800_R8","doi-asserted-by":"crossref","first-page":"871","DOI":"10.1002\/jcb.10694","article-title":"High dose M-CSF partially rescues the Dap12\u2212\/\u2212 osteoclast phenotype","volume":"90","author":"Faccio","year":"2003","journal-title":"J. Cell. Biochem."},{"key":"2021042621083641800_R9","doi-asserted-by":"crossref","first-page":"2245","DOI":"10.1359\/JBMR.050816","article-title":"Regulation of osteoclast apoptosis and motility by small GTPase binding protein Rac1","volume":"20","author":"Fukuda","year":"2005","journal-title":"J. Bone Miner. Res."},{"key":"2021042621083641800_R10","doi-asserted-by":"crossref","first-page":"445","DOI":"10.1126\/science.1088485","article-title":"Hematopoietic Cell Regulation by Rac1 and Rac2 Guanosine Triphosphatases","volume":"302","author":"Gu","year":"2003","journal-title":"Science"},{"key":"2021042621083641800_R11","doi-asserted-by":"crossref","first-page":"20384","DOI":"10.1074\/jbc.272.33.20384","article-title":"Characterization of RAC3, a Novel Member of the Rho Family","volume":"272","author":"Haataja","year":"1997","journal-title":"J. Biol. Chem."},{"key":"2021042621083641800_R12","doi-asserted-by":"crossref","first-page":"690","DOI":"10.1038\/nrm2476","article-title":"Mammalian Rho GTPases: new insights into their functions from in vivo studies","volume":"9","author":"Heasman","year":"2008","journal-title":"Nat. Rev. Mol. Cell. Biol."},{"key":"2021042621083641800_R13","doi-asserted-by":"crossref","first-page":"499","DOI":"10.1359\/JBMR.0301238","article-title":"Actin-related protein 2\/3 complex is required for actin ring formation","volume":"19","author":"Hurst","year":"2004","journal-title":"J. Bone Miner. Res."},{"key":"2021042621083641800_R14","doi-asserted-by":"crossref","first-page":"1981","DOI":"10.1172\/JCI39650","article-title":"Cdc42 regulates bone modeling and remodeling in mice by modulating RANKL\/M-CSF signaling and osteoclast polarization","volume":"120","author":"Ito","year":"2010","journal-title":"J. Clin. Invest."},{"key":"2021042621083641800_R15","doi-asserted-by":"crossref","first-page":"247","DOI":"10.1146\/annurev.cellbio.21.020604.150721","article-title":"Rho GTPases: biochemistry and biology","volume":"21","author":"Jaffe","year":"2005","journal-title":"Annu. Rev. Cell Dev. Biol."},{"key":"2021042621083641800_R16","doi-asserted-by":"crossref","first-page":"433","DOI":"10.1172\/JCI8905","article-title":"Mice lacking \u03b23 integrins are osteosclerotic because of dysfunctional osteoclasts","volume":"105","author":"McHugh","year":"2000","journal-title":"J. Clin. Invest."},{"key":"2021042621083641800_R17","doi-asserted-by":"crossref","first-page":"18","DOI":"10.1159\/000015583","article-title":"The small GTPase RAC3 gene is located within chromosome band 17q25.3 outside and telomeric of a region commonly deleted in breast and ovarian tumours","volume":"89","author":"Morris","year":"2000","journal-title":"Cytogenet. Cell Genet."},{"key":"2021042621083641800_R18","doi-asserted-by":"crossref","first-page":"841","DOI":"10.1091\/mbc.9.4.841","article-title":"Arp2\/3 complex from Acanthamoeba binds profilin and cross-links actin filaments","volume":"9","author":"Mullins","year":"1998","journal-title":"Mol. Biol. Cell"},{"key":"2021042621083641800_R19","doi-asserted-by":"crossref","first-page":"811","DOI":"10.1016\/j.cell.2007.07.025","article-title":"Estrogen prevents bone loss via estrogen receptor \u03b1 and induction of Fas ligand in osteoclasts","volume":"130","author":"Nakamura","year":"2007","journal-title":"Cell"},{"key":"2021042621083641800_R20","doi-asserted-by":"crossref","first-page":"1804","DOI":"10.4049\/jimmunol.0804206","article-title":"SLP-76 couples Syk to the osteoclast cytoskeleton","volume":"183","author":"Reeve","year":"2009","journal-title":"J. Immunol."},{"key":"2021042621083641800_R21","doi-asserted-by":"crossref","first-page":"183","DOI":"10.1016\/S1074-7613(00)80019-9","article-title":"Deficiency of the hematopoietic cell-specific Rho family GTPase Rac2 is characterized by abnormalities in neutrophil function and host defense","volume":"10","author":"Roberts","year":"1999","journal-title":"Immunity"},{"key":"2021042621083641800_R22","doi-asserted-by":"crossref","first-page":"1290","DOI":"10.1016\/j.bone.2006.06.012","article-title":"Activated c-Fms recruits Vav and Rac during CSF-1-induced cytoskeletal remodeling and spreading in osteoclasts","volume":"39","author":"Sakai","year":"2006","journal-title":"Bone"},{"key":"2021042621083641800_R23","doi-asserted-by":"crossref","first-page":"459","DOI":"10.1016\/j.ejcb.2008.01.001","article-title":"Actin cytoskeletal organisation in osteoclasts: a model to decipher transmigration and matrix degradation","volume":"87","author":"Saltel","year":"2008","journal-title":"Eur. J. Cell Biol."},{"key":"2021042621083641800_R24","doi-asserted-by":"crossref","first-page":"693","DOI":"10.1016\/0092-8674(91)90499-O","article-title":"Targeted disruption of the c-src proto-oncogene leads to osteopetrosis in mice","volume":"64","author":"Soriano","year":"1991","journal-title":"Cell"},{"key":"2021042621083641800_R25","doi-asserted-by":"crossref","first-page":"3427","DOI":"10.1038\/sj.onc.1202595","article-title":"Rac1 is required for the formation of three germ layers during gastrulation","volume":"17","author":"Sugihara","year":"1998","journal-title":"Oncogene"},{"key":"2021042621083641800_R26","doi-asserted-by":"crossref","first-page":"427","DOI":"10.2353\/ajpath.2007.060834","article-title":"Osteoclasts: what do they do and how do they do it?","volume":"170","author":"Teitelbaum","year":"2007","journal-title":"Am. J. Pathol."},{"key":"2021042621083641800_R27","doi-asserted-by":"crossref","first-page":"2839","DOI":"10.1056\/NEJMra040952","article-title":"Osteopetrosis","volume":"351","author":"Tolar","year":"2004","journal-title":"N. Engl. J. Med."},{"key":"2021042621083641800_R28","doi-asserted-by":"crossref","first-page":"260","DOI":"10.1359\/jbmr.071013","article-title":"Identifying the relative contributions of Rac1 and Rac2 to osteoclastogenesis","volume":"23","author":"Wang","year":"2008","journal-title":"J. Bone Miner. Res."},{"key":"2021042621083641800_R29","doi-asserted-by":"crossref","first-page":"2749","DOI":"10.1242\/jcs.03024","article-title":"Rac1 and Rac2 regulate macrophage morphology but are not essential for migration","volume":"119","author":"Wheeler","year":"2006","journal-title":"J. Cell Sci."},{"key":"2021042621083641800_R30","doi-asserted-by":"crossref","first-page":"914","DOI":"10.1016\/j.devcel.2008.03.022","article-title":"Synaptotagmin VII regulates bone remodeling by modulating osteoclast and osteoblast secretion","volume":"14","author":"Zhao","year":"2008","journal-title":"Dev. Cell"},{"key":"2021042621083641800_R31","doi-asserted-by":"crossref","first-page":"771","DOI":"10.1210\/me.2004-0161","article-title":"Unoccupied \u03b1v\u03b23 integrin regulates osteoclast apoptosis by transmitting a positive death signal","volume":"19","author":"Zhao","year":"2005","journal-title":"Mol. Endocrinol."},{"key":"2021042621083641800_R32","doi-asserted-by":"crossref","first-page":"877","DOI":"10.1083\/jcb.200611083","article-title":"Syk, c-Src, the \u03b1v\u03b23 integrin, and ITAM immunoreceptors, in concert, regulate osteoclastic bone resorption","volume":"176","author":"Zou","year":"2007","journal-title":"J. Cell Biol."},{"key":"2021042621083641800_R33","doi-asserted-by":"crossref","first-page":"2955","DOI":"10.1242\/jcs.069872","article-title":"Cytoskeletal dysfunction dominates in DAP12-deficient osteoclasts","volume":"123","author":"Zou","year":"2010","journal-title":"J. Cell Sci."}],"container-title":["Journal of Cell Science"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/journals.biologists.com\/jcs\/article-pdf\/124\/22\/3811\/1442558\/3811.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"http:\/\/journals.biologists.com\/jcs\/article-pdf\/124\/22\/3811\/1442558\/3811.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,4,26]],"date-time":"2021-04-26T22:44:15Z","timestamp":1619477055000},"score":1,"resource":{"primary":{"URL":"https:\/\/journals.biologists.com\/jcs\/article\/124\/22\/3811\/64653\/Rac-deletion-in-osteoclasts-causes-severe"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2011,11,15]]},"references-count":33,"journal-issue":{"issue":"22","published-print":{"date-parts":[[2011,11,15]]}},"URL":"https:\/\/doi.org\/10.1242\/jcs.086280","relation":{},"ISSN":["1477-9137","0021-9533"],"issn-type":[{"value":"1477-9137","type":"electronic"},{"value":"0021-9533","type":"print"}],"subject":[],"published":{"date-parts":[[2011,11,15]]}}}