{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,5]],"date-time":"2026-10-05T09:04:14Z","timestamp":1791191054307,"version":"4.1.0"},"reference-count":51,"publisher":"Rockefeller University Press","issue":"5","content-domain":{"domain":["rupress.org"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2011,3,7]]},"abstract":"<jats:p>The blood cell\u2013specific kindlin-3 protein is required to activate leukocyte and platelet integrins. In line with this function, mutations in the KINDLIN-3 gene in man cause immunodeficiency and severe bleeding. Some patients also suffer from osteopetrosis, but the underlying mechanism leading to abnormal bone turnover is unknown. Here we show that kindlin-3\u2013deficient mice develop severe osteopetrosis because of profound adhesion and spreading defects in bone-resorbing osteoclasts. Mechanistically, loss of kindlin-3 impairs the activation of \u03b21, \u03b22, and \u03b23 integrin classes expressed on osteoclasts, which in turn abrogates the formation of podosomes and sealing zones required for bone resorption. In agreement with these findings, genetic ablation of all integrin classes abolishes the development of podosomes, mimicking kindlin-3 deficiency. Although loss of single integrin classes gives rise to podosomes, their resorptive activity is impaired. These findings show that osteoclasts require their entire integrin repertoire to be regulated by kindlin-3 to orchestrate bone homeostasis.<\/jats:p>","DOI":"10.1083\/jcb.201007141","type":"journal-article","created":{"date-parts":[[2011,3,2]],"date-time":"2011-03-02T11:32:12Z","timestamp":1299065532000},"page":"883-897","update-policy":"https:\/\/doi.org\/10.1083\/jcb.crossmarkpolicy","source":"Crossref","is-referenced-by-count":167,"title":["Kindlin-3\u2013mediated signaling from multiple integrin classes is required for osteoclast-mediated bone resorption"],"prefix":"10.1083","volume":"192","author":[{"given":"Sarah","family":"Schmidt","sequence":"first","affiliation":[{"name":"Max Planck Institute of Biochemistry, D-82152 Martinsried, Germany 1"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Inaam","family":"Nakchbandi","sequence":"additional","affiliation":[{"name":"Max Planck Institute of Biochemistry, D-82152 Martinsried, Germany 1"},{"name":"University of Heidelberg, D-69120 Heidelberg, Germany 2"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Raphael","family":"Ruppert","sequence":"additional","affiliation":[{"name":"Max Planck Institute of Biochemistry, D-82152 Martinsried, Germany 1"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nina","family":"Kawelke","sequence":"additional","affiliation":[{"name":"Max Planck Institute of Biochemistry, D-82152 Martinsried, Germany 1"},{"name":"University of Heidelberg, D-69120 Heidelberg, Germany 2"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael W.","family":"Hess","sequence":"additional","affiliation":[{"name":"Innsbruck Medical University, Division of Histology and Embryology, A-6020 Innsbruck, Austria 3"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kristian","family":"Pfaller","sequence":"additional","affiliation":[{"name":"Innsbruck Medical University, Division of Histology and Embryology, A-6020 Innsbruck, Austria 3"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pierre","family":"Jurdic","sequence":"additional","affiliation":[{"name":"University of Lyon, Ecole Normale Sup\u00e9rieure de Lyon, 69364 Lyon, France 4"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Reinhard","family":"F\u00e4ssler","sequence":"additional","affiliation":[{"name":"Max Planck Institute of Biochemistry, D-82152 Martinsried, Germany 1"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Markus","family":"Moser","sequence":"additional","affiliation":[{"name":"Max Planck Institute of Biochemistry, D-82152 Martinsried, Germany 1"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"291","published-online":{"date-parts":[[2011,2,28]]},"reference":[{"key":"2023072901350135700_bib1","doi-asserted-by":"publisher","first-page":"4899","DOI":"10.1091\/mbc.E07-04-0378","article-title":"CD44 and beta3 integrin organize two functionally distinct actin-based domains in osteoclasts","volume":"18","author":"Chabadel","year":"2007","journal-title":"Mol. Biol. Cell."},{"key":"2023072901350135700_bib2","doi-asserted-by":"publisher","first-page":"942","DOI":"10.1161\/CIRCRESAHA.107.164376","article-title":"Phosphatidylinositol-3-kinase-gamma is integral to homing functions of progenitor cells","volume":"102","author":"Chavakis","year":"2008","journal-title":"Circ. Res."},{"key":"2023072901350135700_bib3","doi-asserted-by":"publisher","first-page":"889","DOI":"10.1083\/jcb.200604060","article-title":"Genetic analysis of beta1 integrin \u201cactivation motifs\u201d in mice","volume":"174","author":"Czuchra","year":"2006","journal-title":"J. Cell Biol."},{"key":"2023072901350135700_bib4","doi-asserted-by":"publisher","first-page":"407","DOI":"10.1091\/mbc.E02-07-0389","article-title":"Podosomes display actin turnover and dynamic self-organization in osteoclasts expressing actin-green fluorescent protein","volume":"14","author":"Destaing","year":"2003","journal-title":"Mol. Biol. Cell."},{"key":"2023072901350135700_bib5","doi-asserted-by":"publisher","first-page":"2901","DOI":"10.1242\/jcs.02425","article-title":"A novel Rho-mDia2-HDAC6 pathway controls podosome patterning through microtubule acetylation in osteoclasts","volume":"118","author":"Destaing","year":"2005","journal-title":"J. Cell Sci."},{"key":"2023072901350135700_bib6","doi-asserted-by":"publisher","first-page":"394","DOI":"10.1091\/mbc.E07-03-0227","article-title":"The tyrosine kinase activity of c-Src regulates actin dynamics and organization of podosomes in osteoclasts","volume":"19","author":"Destaing","year":"2008","journal-title":"Mol. Biol. Cell."},{"key":"2023072901350135700_bib7","doi-asserted-by":"crossref","first-page":"14853","DOI":"10.1016\/S0021-9258(17)36541-9","article-title":"Dephosphorylation of osteopontin and bone sialoprotein by osteoclastic tartrate-resistant acid phosphatase. Modulation of osteoclast adhesion in vitro","volume":"269","author":"Ek-Rylander","year":"1994","journal-title":"J. Biol. Chem."},{"key":"2023072901350135700_bib8","doi-asserted-by":"publisher","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 beta3 integrin","volume":"162","author":"Faccio","year":"2003","journal-title":"J. Cell Biol."},{"key":"2023072901350135700_bib9","doi-asserted-by":"crossref","first-page":"749","DOI":"10.1172\/JCI200316924","article-title":"c-Fms and the alphavbeta3 integrin collaborate during osteoclast differentiation","volume":"111","author":"Faccio","year":"2003","journal-title":"J. Clin. Invest."},{"key":"2023072901350135700_bib10","doi-asserted-by":"publisher","first-page":"526","DOI":"10.1016\/0014-4827(92)90305-R","article-title":"RGD-directed attachment of isolated rat osteoclasts to osteopontin, bone sialoprotein, and fibronectin","volume":"201","author":"Flores","year":"1992","journal-title":"Exp. Cell Res."},{"key":"2023072901350135700_bib11","doi-asserted-by":"crossref","first-page":"715","DOI":"10.1042\/bj2320715","article-title":"Isolation and characterization of two sialoproteins present only in bone calcified matrix","volume":"232","author":"Franz\u00e9n","year":"1985","journal-title":"Biochem. J."},{"key":"2023072901350135700_bib12","doi-asserted-by":"publisher","first-page":"1053","DOI":"10.1083\/jcb.200701148","article-title":"Defective microtubule-dependent podosome organization in osteoclasts leads to increased bone density in Pyk2(-\/-) mice","volume":"178","author":"Gil-Henn","year":"2007","journal-title":"J. Cell Biol."},{"key":"2023072901350135700_bib13","doi-asserted-by":"publisher","first-page":"189","DOI":"10.1136\/mp.52.4.189","article-title":"CD44 cell adhesion molecules","volume":"52","author":"Goodison","year":"1999","journal-title":"MP, Mol. Pathol."},{"key":"2023072901350135700_bib14","doi-asserted-by":"publisher","first-page":"370","DOI":"10.1210\/jcem-71-2-370","article-title":"Rate and concentration dependence of parathyroid hormone dynamics during stepwise changes in serum ionized calcium in normal humans","volume":"71","author":"Grant","year":"1990","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"2023072901350135700_bib15","doi-asserted-by":"publisher","first-page":"77","DOI":"10.1016\/j.ab.2004.02.002","article-title":"An Alizarin red-based assay of mineralization by adherent cells in culture: comparison with cetylpyridinium chloride extraction","volume":"329","author":"Gregory","year":"2004","journal-title":"Anal. Biochem."},{"key":"2023072901350135700_bib16","doi-asserted-by":"publisher","first-page":"317","DOI":"10.1016\/S8756-3282(96)00223-2","article-title":"Beta 1 integrins and osteoclast function: involvement in collagen recognition and bone resorption","volume":"19","author":"Helfrich","year":"1996","journal-title":"Bone."},{"key":"2023072901350135700_bib17","doi-asserted-by":"publisher","first-page":"545","DOI":"10.1034\/j.1600-0854.2000.010704.x","article-title":"The production of \u2018cell cortices\u2019 for light and electron microscopy","volume":"1","author":"Heuser","year":"2000","journal-title":"Traffic."},{"key":"2023072901350135700_bib18","doi-asserted-by":"publisher","first-page":"229","DOI":"10.1172\/JCI5487","article-title":"Beta3-integrin-deficient mice are a model for Glanzmann thrombasthenia showing placental defects and reduced survival","volume":"103","author":"Hodivala-Dilke","year":"1999","journal-title":"J. Clin. Invest."},{"key":"2023072901350135700_bib19","doi-asserted-by":"publisher","first-page":"195","DOI":"10.1016\/j.ejcb.2005.09.008","article-title":"Podosome and sealing zone: specificity of the osteoclast model","volume":"85","author":"Jurdic","year":"2006","journal-title":"Eur. J. Cell Biol."},{"key":"2023072901350135700_bib20","doi-asserted-by":"publisher","first-page":"117","DOI":"10.1007\/s10875-008-9226-z","article-title":"The clinical spectrum of leukocyte adhesion deficiency (LAD) III due to defective CalDAG-GEF1","volume":"29","author":"Kilic","year":"2009","journal-title":"J. Clin. Immunol."},{"key":"2023072901350135700_bib21","doi-asserted-by":"publisher","first-page":"353","DOI":"10.1016\/j.cell.2008.05.033","article-title":"SILAC mouse for quantitative proteomics uncovers kindlin-3 as an essential factor for red blood cell function","volume":"134","author":"Kr\u00fcger","year":"2008","journal-title":"Cell."},{"key":"2023072901350135700_bib22","doi-asserted-by":"publisher","first-page":"1427","DOI":"10.1126\/science.7660125","article-title":"Inducible gene targeting in mice","volume":"269","author":"K\u00fchn","year":"1995","journal-title":"Science."},{"key":"2023072901350135700_bib23","doi-asserted-by":"publisher","first-page":"4740","DOI":"10.1182\/blood-2008-10-182154","article-title":"LAD-1\/variant syndrome is caused by mutations in FERMT3","volume":"113","author":"Kuijpers","year":"2009","journal-title":"Blood."},{"key":"2023072901350135700_bib24","doi-asserted-by":"publisher","first-page":"1203","DOI":"10.1038\/embor.2008.202","article-title":"Kindlins: essential regulators of integrin signalling and cell-matrix adhesion","volume":"9","author":"Larjava","year":"2008","journal-title":"EMBO Rep."},{"key":"2023072901350135700_bib25","doi-asserted-by":"publisher","first-page":"397","DOI":"10.1101\/gad.1758709","article-title":"Genetic and cell biological analysis of integrin outside-in signaling","volume":"23","author":"Legate","year":"2009","journal-title":"Genes Dev."},{"key":"2023072901350135700_bib26","doi-asserted-by":"publisher","first-page":"376","DOI":"10.1016\/S0962-8924(03)00128-4","article-title":"Podosomes: adhesion hot-spots of invasive cells","volume":"13","author":"Linder","year":"2003","journal-title":"Trends Cell Biol."},{"key":"2023072901350135700_bib27","doi-asserted-by":"publisher","first-page":"2079","DOI":"10.1242\/jcs.02390","article-title":"Podosomes at a glance","volume":"118","author":"Linder","year":"2005","journal-title":"J. Cell Sci."},{"key":"2023072901350135700_bib28","doi-asserted-by":"publisher","first-page":"e179","DOI":"10.1371\/journal.pone.0000179","article-title":"The architecture of the adhesive apparatus of cultured osteoclasts: from podosome formation to sealing zone assembly","volume":"2","author":"Luxenburg","year":"2007","journal-title":"PLoS ONE."},{"key":"2023072901350135700_bib29","doi-asserted-by":"publisher","first-page":"313","DOI":"10.1038\/nm.1917","article-title":"A point mutation in KINDLIN3 ablates activation of three integrin subfamilies in humans","volume":"15","author":"Malinin","year":"2009","journal-title":"Nat. Med."},{"key":"2023072901350135700_bib30","doi-asserted-by":"publisher","first-page":"4834","DOI":"10.1182\/blood-2009-08-238709","article-title":"Two mutations in the KINDLIN3 gene of a new leukocyte adhesion deficiency III patient reveal distinct effects on leukocyte function in vitro","volume":"115","author":"McDowall","year":"2010","journal-title":"Blood."},{"key":"2023072901350135700_bib31","doi-asserted-by":"publisher","first-page":"433","DOI":"10.1172\/JCI8905","article-title":"Mice lacking beta3 integrins are osteosclerotic because of dysfunctional osteoclasts","volume":"105","author":"McHugh","year":"2000","journal-title":"J. Clin. Invest."},{"key":"2023072901350135700_bib32","doi-asserted-by":"publisher","first-page":"325","DOI":"10.1038\/nm1722","article-title":"Kindlin-3 is essential for integrin activation and platelet aggregation","volume":"14","author":"Moser","year":"2008","journal-title":"Nat. Med."},{"key":"2023072901350135700_bib33","doi-asserted-by":"publisher","first-page":"300","DOI":"10.1038\/nm.1921","article-title":"Kindlin-3 is required for beta2 integrin-mediated leukocyte adhesion to endothelial cells","volume":"15","author":"Moser","year":"2009","journal-title":"Nat. Med."},{"key":"2023072901350135700_bib34","doi-asserted-by":"publisher","first-page":"895","DOI":"10.1126\/science.1163865","article-title":"The tail of integrins, talin, and kindlins","volume":"324","author":"Moser","year":"2009","journal-title":"Science."},{"key":"2023072901350135700_bib35","doi-asserted-by":"crossref","first-page":"5701","DOI":"10.1128\/jvi.70.8.5701-5705.1996","article-title":"The pCL vector system: rapid production of helper-free, high-titer, recombinant retroviruses","volume":"70","author":"Naviaux","year":"1996","journal-title":"J. Virol."},{"key":"2023072901350135700_bib36","doi-asserted-by":"publisher","first-page":"595","DOI":"10.1002\/jbmr.5650020617","article-title":"Bone histomorphometry: standardization of nomenclature, symbols, and units","volume":"2","author":"Parfitt","year":"1987","journal-title":"J. Bone Miner. Res."},{"key":"2023072901350135700_bib37","doi-asserted-by":"publisher","first-page":"12227","DOI":"10.1073\/pnas.220399597","article-title":"Suppression of angiogenesis by lentiviral delivery of PEX, a noncatalytic fragment of matrix metalloproteinase 2","volume":"97","author":"Pfeifer","year":"2000","journal-title":"Proc. Natl. Acad. Sci. USA."},{"key":"2023072901350135700_bib38","doi-asserted-by":"publisher","first-page":"323","DOI":"10.1097\/MOH.0b013e32832ea389","article-title":"Kindling the flame of integrin activation and function with kindlins","volume":"16","author":"Plow","year":"2009","journal-title":"Curr. Opin. Hematol."},{"key":"2023072901350135700_bib39","doi-asserted-by":"publisher","first-page":"33","DOI":"10.1038\/nrm1004","article-title":"CD44: from adhesion molecules to signalling regulators","volume":"4","author":"Ponta","year":"2003","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"2023072901350135700_bib40","doi-asserted-by":"publisher","first-page":"653","DOI":"10.1016\/S1074-7613(00)80216-2","article-title":"Fetal and adult hematopoietic stem cells require beta1 integrin function for colonizing fetal liver, spleen, and bone marrow","volume":"12","author":"Potocnik","year":"2000","journal-title":"Immunity."},{"key":"2023072901350135700_bib41","doi-asserted-by":"publisher","first-page":"1657","DOI":"10.1359\/jbmr.060718","article-title":"Alpha9beta1: a novel osteoclast integrin that regulates osteoclast formation and function","volume":"21","author":"Rao","year":"2006","journal-title":"J. Bone Miner. Res."},{"key":"2023072901350135700_bib42","doi-asserted-by":"publisher","first-page":"88","DOI":"10.1111\/j.0105-2896.2005.00331.x","article-title":"alphavbeta3 and macrophage colony-stimulating factor: partners in osteoclast biology","volume":"208","author":"Ross","year":"2005","journal-title":"Immunol. Rev."},{"key":"2023072901350135700_bib43","doi-asserted-by":"crossref","first-page":"180","DOI":"10.1002\/pbc.22386","article-title":"Leukocyte adhesion deficiency-III in an African-American patient","volume":"55","author":"Sabnis","year":"2010","journal-title":"Pediatr. Blood Cancer."},{"key":"2023072901350135700_bib44","doi-asserted-by":"publisher","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":"2023072901350135700_bib45","doi-asserted-by":"publisher","first-page":"119","DOI":"10.1084\/jem.188.1.119","article-title":"Spontaneous skin ulceration and defective T cell function in CD18 null mice","volume":"188","author":"Scharffetter-Kochanek","year":"1998","journal-title":"J. Exp. Med."},{"key":"2023072901350135700_bib46","doi-asserted-by":"publisher","first-page":"345","DOI":"10.1210\/er.20.3.345","article-title":"Modulation of osteoclast differentiation and function by the new members of the tumor necrosis factor receptor and ligand families","volume":"20","author":"Suda","year":"1999","journal-title":"Endocr. Rev."},{"key":"2023072901350135700_bib47","doi-asserted-by":"publisher","first-page":"306","DOI":"10.1038\/nm.1931","article-title":"Leukocyte adhesion deficiency-III is caused by mutations in KINDLIN3 affecting integrin activation","volume":"15","author":"Svensson","year":"2009","journal-title":"Nat. Med."},{"key":"2023072901350135700_bib48","doi-asserted-by":"publisher","first-page":"638","DOI":"10.1038\/nrg1122","article-title":"Genetic regulation of osteoclast development and function","volume":"4","author":"Teitelbaum","year":"2003","journal-title":"Nat. Rev. Genet."},{"key":"2023072901350135700_bib49","doi-asserted-by":"publisher","first-page":"3142","DOI":"10.1016\/j.yexcr.2006.06.030","article-title":"The Kindlins: subcellular localization and expression during murine development","volume":"312","author":"Ussar","year":"2006","journal-title":"Exp. Cell Res."},{"key":"2023072901350135700_bib50","doi-asserted-by":"crossref","first-page":"207","DOI":"10.1016\/S0925-4439(03)00035-8","article-title":"URP1: a member of a novel family of PH and FERM domain-containing membrane-associated proteins is significantly over-expressed in lung and colon carcinomas","volume":"1637","author":"Weinstein","year":"2003","journal-title":"Biochim. Biophys. Acta."},{"key":"2023072901350135700_bib51","doi-asserted-by":"crossref","first-page":"687","DOI":"10.1242\/dev.116.3.687","article-title":"An X-linked human collagen transgene escapes X inactivation in a subset of cells","volume":"116","author":"Wu","year":"1992","journal-title":"Development."}],"container-title":["Journal of Cell Biology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/rupress.org\/jcb\/article-pdf\/192\/5\/883\/1854809\/jcb_201007141.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/rupress.org\/jcb\/article-pdf\/192\/5\/883\/1854809\/jcb_201007141.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,7,28]],"date-time":"2023-07-28T21:35:39Z","timestamp":1690580139000},"score":1,"resource":{"primary":{"URL":"https:\/\/rupress.org\/jcb\/article\/192\/5\/883\/36392\/Kindlin-3-mediated-signaling-from-multiple"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2011,2,28]]},"references-count":51,"journal-issue":{"issue":"5","published-print":{"date-parts":[[2011,3,7]]}},"URL":"https:\/\/doi.org\/10.1083\/jcb.201007141","relation":{"has-review":[{"id-type":"doi","id":"10.3410\/f.11256959.12250055","asserted-by":"object"}]},"ISSN":["1540-8140","0021-9525"],"issn-type":[{"value":"1540-8140","type":"electronic"},{"value":"0021-9525","type":"print"}],"subject":[],"published":{"date-parts":[[2011,2,28]]}}}