{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,1]],"date-time":"2026-07-01T16:57:27Z","timestamp":1782925047287,"version":"3.54.5"},"reference-count":48,"publisher":"Oxford University Press (OUP)","issue":"5","license":[{"start":{"date-parts":[[2018,1,3]],"date-time":"2018-01-03T00:00:00Z","timestamp":1514937600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/journals\/pages\/open_access\/funder_policies\/chorus\/standard_publication_model"}],"funder":[{"DOI":"10.13039\/501100000024","name":"Canadian Institutes of Health Research","doi-asserted-by":"publisher","award":["86655"],"award-info":[{"award-number":["86655"]}],"id":[{"id":"10.13039\/501100000024","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2018,5,1]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n               <jats:sec>\n                  <jats:title>\u2003<\/jats:title>\n                  <jats:p>Ostm1 mutations are responsible for the most severe form of osteopetrosis in human and mice. To gain insight into Ostm1 cellular functions, we engineered a conditional in-frame deletion of the Ostm1 transmembrane domain and generated the first Ostm1 mouse model with a human mutation. Systemic targeting of Ostm1 loss of transmembrane domain produced osteopetrosis, as in the null Ostm1 gl\/gl mouse. Significantly, conditional osteoclast targeting of Ostm1 resulted in similar osteopetrosis, thereby demonstrating that the intrinsic Ostm1 osteoclast deficiency is solely responsible for the mouse phenotype. Our analysis showed oversized osteoclasts with enhanced multinucleation associated with stimulation of intracellular calcium levels, of Nfatc1 nuclear re-localization, and of specific downstream Nfatc1 target genes, providing compelling evidence that Ostm1 is a negative regulator of preosteoclast fusion. Moreover, mature OCs with Ostm1 loss of transmembrane domain show appropriate levels of intracellular acidification but an altered distribution pattern, highlighting misregulation of endolysosome localization and dispersion. Consistently, the hydrolases tartrate-resistant acid phosphatase (TRAP) and cathepsin K (Ctsk) normally produced are sequestered within the osteoclasts and are not extracellularly secreted. These studies defined bifunctional roles for Ostm1 as a major regulator of preosteoclast cytoskeletal rearrangements toward cell multinucleation and of mature osteoclast intracellular lysosomal trafficking and exocytosis mechanism, both of which are essential for bone resorption. Importantly, these Ostm1 molecular and regulatory functions could serve as preclinical targets in this mouse model toward osteoclastogenic pathologies as osteoporosis and inflammation-induced bone loss. \u00a9 2018 American Society for Bone and Mineral Research.<\/jats:p>\n               <\/jats:sec>","DOI":"10.1002\/jbmr.3378","type":"journal-article","created":{"date-parts":[[2018,1,3]],"date-time":"2018-01-03T10:41:43Z","timestamp":1514976103000},"page":"888-898","source":"Crossref","is-referenced-by-count":28,"title":["Ostm1 Bifunctional Roles in Osteoclast Maturation: Insights From a Mouse Model Mimicking a Human OSTM1 Mutation"],"prefix":"10.1093","volume":"33","author":[{"given":"Monica","family":"Pata","sequence":"first","affiliation":[{"name":"Institut de Recherches Cliniques de Montr\u00e9al (IRCM)Montr\u00e9alQu\u00e9becCanada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jean","family":"Vacher","sequence":"additional","affiliation":[{"name":"Department of MedicineDivision of Experimental MedicineMcGill UniversityMontr\u00e9alQu\u00e9becCanada"},{"name":"D\u00e9partement de M\u00e9decineUniversit\u00e9 de Montr\u00e9alMontr\u00e9alQu\u00e9becCanada"},{"name":"Institut de Recherches Cliniques de Montr\u00e9al (IRCM)Montr\u00e9alQu\u00e9becCanada"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2018,1,3]]},"reference":[{"key":"2024021014341580400_jbmr3378-bib-0001","doi-asserted-by":"crossref","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":"2024021014341580400_jbmr3378-bib-0002","doi-asserted-by":"crossref","first-page":"791","DOI":"10.1038\/nm1593","article-title":"Skeletal remodeling in health and disease","volume":"13","author":"Zaidi","year":"2007","journal-title":"Nat Med"},{"key":"2024021014341580400_jbmr3378-bib-0003","doi-asserted-by":"crossref","first-page":"337","DOI":"10.1038\/nature01658","article-title":"Osteoclast differentiation and activation","volume":"423","author":"Boyle","year":"2003","journal-title":"Nature"},{"key":"2024021014341580400_jbmr3378-bib-0004","first-page":"666","article-title":"Osteoclast-specific cathepsin K deletion stimulates S1P-dependent bone formation","volume":"123","author":"Lotinun","year":"2013","journal-title":"J Clin Invest"},{"issue":"5","key":"2024021014341580400_jbmr3378-bib-0005","doi-asserted-by":"crossref","first-page":"2030","DOI":"10.1172\/JCI93356","article-title":"Inflammatory osteolysis: a conspiracy against bone","volume":"127","author":"Mbalaviele","year":"2017","journal-title":"J Clin Invest"},{"issue":"27","key":"2024021014341580400_jbmr3378-bib-0006","doi-asserted-by":"crossref","first-page":"2839","DOI":"10.1056\/NEJMra040952","volume":"351","author":"Tolar","year":"2004","journal-title":"Osteopetrosis. N Engl J Med"},{"key":"2024021014341580400_jbmr3378-bib-0007","doi-asserted-by":"crossref","first-page":"522","DOI":"10.1038\/nrendo.2013.137","article-title":"Osteopetrosis: genetics, treatment and new insights into osteoclast function","volume":"9","author":"Sobacchi","year":"2013","journal-title":"Nat Rev Endocrinol"},{"issue":"4","key":"2024021014341580400_jbmr3378-bib-0008","doi-asserted-by":"crossref","first-page":"399","DOI":"10.1038\/nm842","article-title":"Grey-lethal mutation induces severe malignant autosomal recessive osteopetrosis in mouse and human","volume":"9","author":"Chalhoub","year":"2003","journal-title":"Nat Med"},{"issue":"7","key":"2024021014341580400_jbmr3378-bib-0009","doi-asserted-by":"crossref","first-page":"1194","DOI":"10.1359\/JBMR.040407","article-title":"Severe malignant osteopetrosis due to a Gl gene mutation","volume":"19","author":"Quarello","year":"2004","journal-title":"J Bone Miner Res"},{"issue":"2","key":"2024021014341580400_jbmr3378-bib-0010","doi-asserted-by":"crossref","first-page":"87","DOI":"10.1046\/j.1365-2990.2003.00474.x","article-title":"Neurological aspects of osteopetrosis","volume":"29","author":"Steward","year":"2003","journal-title":"Neuropathol Appl Neurobiol"},{"issue":"45","key":"2024021014341580400_jbmr3378-bib-0011","doi-asserted-by":"crossref","first-page":"30522","DOI":"10.1074\/jbc.M805242200","article-title":"OSTM1 bone defect reveals an intercellular hematopoietic crosstalk","volume":"283","author":"Pata","year":"2008","journal-title":"J Biol Chem"},{"issue":"20","key":"2024021014341580400_jbmr3378-bib-0012","doi-asserted-by":"crossref","first-page":"13912","DOI":"10.1074\/jbc.M113.537233","article-title":"Severe neurodegeneration with impaired autophagy mechanism triggered by Ostm1 deficiency","volume":"289","author":"H\u00e9raud","year":"2014","journal-title":"J Biol Chem"},{"issue":"2","key":"2024021014341580400_jbmr3378-bib-0013","doi-asserted-by":"crossref","first-page":"292","DOI":"10.1016\/j.bone.2013.04.007","article-title":"Severe neuronopathic autosomal recessive osteopetrosis due to homozygous deletions affecting OSTM1","volume":"55","author":"Ott","year":"2013","journal-title":"Bone"},{"issue":"8","key":"2024021014341580400_jbmr3378-bib-0014","doi-asserted-by":"crossref","first-page":"473","DOI":"10.1002\/ajh.21447","article-title":"A single-center experience in 20 patients with infantile malignant osteopetrosis","volume":"84","author":"Mazzolari","year":"2009","journal-title":"Am J Hematol"},{"issue":"2","key":"2024021014341580400_jbmr3378-bib-0015","doi-asserted-by":"crossref","first-page":"296","DOI":"10.1359\/jbmr.071015","article-title":"Clinical and cellular manifestations of OSTM1 related infantile osteopetrosis","volume":"23","author":"Maranda","year":"2008","journal-title":"J Bone Miner Res"},{"issue":"3","key":"2024021014341580400_jbmr3378-bib-0016","doi-asserted-by":"crossref","first-page":"507","DOI":"10.1128\/MCB.00656-15","article-title":"Role of Ostm1 cytosolic complex with kinesin 5B in intracellular dispersion and trafficking","volume":"36","author":"Pandruvada","year":"2016","journal-title":"Mol Cell Biol"},{"issue":"7","key":"2024021014341580400_jbmr3378-bib-0017","doi-asserted-by":"crossref","first-page":"1098","DOI":"10.1359\/jbmr.060403","article-title":"Mutations in OSTM1 (Grey Lethal) define a particularly severe form of autosomal recessive osteopetrosis with neural involvement","volume":"21","author":"Pangrazio","year":"2006","journal-title":"J Bone Miner Res"},{"key":"2024021014341580400_jbmr3378-bib-0018","doi-asserted-by":"crossref","first-page":"188","DOI":"10.1016\/j.ejmg.2007.01.005","article-title":"Molecular study of six families originating from the middle-east and presenting with autosomal recessive osteopetrosis","volume":"50","author":"Souraty","year":"2007","journal-title":"Eur J Med Genet"},{"key":"2024021014341580400_jbmr3378-bib-0019","doi-asserted-by":"crossref","first-page":"220","DOI":"10.1038\/nature04535","article-title":"ClC-7 requires Ostm1 as a beta-subunit to support bone resorption and lysosomal function","volume":"440","author":"Lange","year":"2006","journal-title":"Nature"},{"key":"2024021014341580400_jbmr3378-bib-0020","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"},{"issue":"5","key":"2024021014341580400_jbmr3378-bib-0021","doi-asserted-by":"crossref","first-page":"513","DOI":"10.1016\/S8756-3282(01)00416-1","article-title":"The mouse osteopetrotic grey-lethal mutation induces a defect in osteoclast maturation\/function","volume":"28","author":"Rajapurohitam","year":"2001","journal-title":"Bone"},{"issue":"5","key":"2024021014341580400_jbmr3378-bib-0022","doi-asserted-by":"crossref","first-page":"1085","DOI":"10.1002\/jcb.20835","article-title":"Secretion of tartrate-resistant acid phosphatase by osteoclasts correlates with resorptive behavior","volume":"98","author":"Kirstein","year":"2006","journal-title":"J Cell Biochem"},{"key":"2024021014341580400_jbmr3378-bib-0023","doi-asserted-by":"crossref","first-page":"466","DOI":"10.1016\/j.cmet.2011.08.013","article-title":"Inositol Polyphosphate 4-phosphatase b as a regulator of bone mass in mice and humans","volume":"14","author":"Ferron","year":"2011","journal-title":"Cell Metab"},{"issue":"7","key":"2024021014341580400_jbmr3378-bib-0024","doi-asserted-by":"crossref","first-page":"1468","DOI":"10.1002\/jbmr.141","article-title":"Guidelines for assessment of bone microstructure in rodents using micro-computed tomography","volume":"25","author":"Bouxsein","year":"2010","journal-title":"J Bone Miner Res"},{"key":"2024021014341580400_jbmr3378-bib-0025","doi-asserted-by":"crossref","first-page":"106","DOI":"10.1002\/1526-968X(200011\/12)28:3\/4<106::AID-GENE30>3.0.CO;2-T","article-title":"Widespread recombinase expression using FLPeR (Flipper) mice","volume":"28","author":"Farley","year":"2000","journal-title":"Genesis"},{"key":"2024021014341580400_jbmr3378-bib-0026","doi-asserted-by":"crossref","first-page":"113","DOI":"10.1002\/(SICI)1526-968X(200002)26:2<113::AID-GENE3>3.0.CO;2-2","article-title":"Epiblast-restricted Cre expression in MORE mice: a tool to distinguish embryonic vs. extra-embryonic gene function","volume":"26","author":"Tallquist","year":"2000","journal-title":"Genesis"},{"key":"2024021014341580400_jbmr3378-bib-0027","doi-asserted-by":"crossref","first-page":"42","DOI":"10.1016\/j.bone.2011.09.038","article-title":"Meox2Cre-mediated disruption of CSF-1 leads to osteopetrosis and osteocyte defects","volume":"50","author":"Harris","year":"2012","journal-title":"Bone"},{"issue":"4","key":"2024021014341580400_jbmr3378-bib-0028","doi-asserted-by":"crossref","first-page":"864","DOI":"10.1002\/jbmr.2733","article-title":"Deletion of rac in mature osteoclasts causes osteopetrosis, an age-dependent change in osteoclast number, and a reduced number of osteoblasts in vivo","volume":"31","author":"Zhu","year":"2016","journal-title":"J Bone Miner Res"},{"issue":"52","key":"2024021014341580400_jbmr3378-bib-0029","doi-asserted-by":"crossref","first-page":"35868","DOI":"10.1074\/jbc.M114.589614","article-title":"Secretion of a truncated osteopetrosis-associated transmembrane protein 1 (Ostm1) mutant inhibits osteoclastogenesis through downregulation of the B lymphocyte-induced maturation protein (Blimp1)\u2013nuclear factor of activated T cells c1 (NFATc1) axis","volume":"289","author":"Shin","year":"2014","journal-title":"J Biol Chem"},{"key":"2024021014341580400_jbmr3378-bib-0030","doi-asserted-by":"crossref","first-page":"241","DOI":"10.1111\/j.1600-065X.2009.00821.x","article-title":"Ca2+-NFATc1 signaling is an essential axis of osteoclast differentiation","volume":"231","author":"Negishi-Koga","year":"2009","journal-title":"Immunol Rev"},{"key":"2024021014341580400_jbmr3378-bib-0031","doi-asserted-by":"crossref","first-page":"889","DOI":"10.1016\/S1534-5807(02)00369-6","article-title":"Induction and activation of the transcription factor NFATc1 (NFAT2) integrate RANKL signaling in terminal differentiation of osteoclasts","volume":"3","author":"Takayanagi","year":"2002","journal-title":"Dev Cell"},{"key":"2024021014341580400_jbmr3378-bib-0032","doi-asserted-by":"crossref","first-page":"1403","DOI":"10.1038\/nm1514","article-title":"v-ATPase V0 subunit d2-deficient mice exhibit impaired osteoclast fusion and increased bone formation","volume":"12","author":"Lee","year":"2006","journal-title":"Nat Med"},{"key":"2024021014341580400_jbmr3378-bib-0033","doi-asserted-by":"crossref","first-page":"176","DOI":"10.1210\/me.2007-0237","article-title":"NFATc1 induces osteoclast fusion via up-regulation of Atp6v0d2 and the dendritic cell-specific transmembrane protein (DC-STAMP)","volume":"222","author":"Kim","year":"2008","journal-title":"Mol Endocrinol"},{"key":"2024021014341580400_jbmr3378-bib-0034","doi-asserted-by":"crossref","first-page":"1289","DOI":"10.1002\/jbmr.1575","article-title":"Osteoclast stimulatory transmembrane protein and dendritic cell-specific transmembrane protein cooperatively modulate cell-cell fusion to form osteoclasts and foreign body giant cells","volume":"27","author":"Miyamoto","year":"2012","journal-title":"J Bone Miner Res"},{"issue":"6)","key":"2024021014341580400_jbmr3378-bib-0035","doi-asserted-by":"crossref","first-page":"e0128275","DOI":"10.1371\/journal.pone.0128275","article-title":"Studies of OC-STAMP in osteoclast fusion: a new knockout mouse model, rescue of cell fusion, and transmembrane topology","volume":"10","author":"Witwicka","year":"2015","journal-title":"PLoS One"},{"key":"2024021014341580400_jbmr3378-bib-0036","doi-asserted-by":"crossref","first-page":"1261","DOI":"10.1084\/jem.20051150","article-title":"Autoamplification of NFATc1 expression determines its essential role in bone homeostasis","volume":"202","author":"Asagiri","year":"2005","journal-title":"J Exp Med"},{"key":"2024021014341580400_jbmr3378-bib-0037","doi-asserted-by":"crossref","first-page":"2210","DOI":"10.1083\/jcb.101.6.2210","article-title":"Cell-mediated extracellular acidification and bone resorption: evidence for a low pH in resorbing lacunae and localization of a 100-kD lysosomal membrane protein at the osteoclast ruffled-border","volume":"101","author":"Baron","year":"1985","journal-title":"J Cell Biol"},{"issue":"4","key":"2024021014341580400_jbmr3378-bib-0038","doi-asserted-by":"crossref","first-page":"589","DOI":"10.1038\/nm.2659","article-title":"Vitamin E decreases bone mass by stimulating osteoclast fusion","volume":"18","author":"Fujita","year":"2012","journal-title":"Nat Med"},{"key":"2024021014341580400_jbmr3378-bib-0039","doi-asserted-by":"crossref","first-page":"1058","DOI":"10.1002\/jcb.22640","article-title":"Recent advances in understanding the mechanisms of osteoclast precursor fusion","volume":"110","author":"Oursler","year":"2010","journal-title":"J Cell Biochem"},{"key":"2024021014341580400_jbmr3378-bib-0040","doi-asserted-by":"crossref","first-page":"345","DOI":"10.1084\/jem.20050645","article-title":"DC-STAMP is essential for cell-cell fusion in osteoclasts and foreign body giant cells","volume":"202","author":"Yagi","year":"2005","journal-title":"J Exp Med"},{"key":"2024021014341580400_jbmr3378-bib-0041","doi-asserted-by":"crossref","first-page":"899","DOI":"10.1016\/j.bbrc.2008.10.076","article-title":"Cell fusion in osteoclasts plays a critical role in controlling bone mass and osteoblastic activity","volume":"377","author":"Iwasaki","year":"2008","journal-title":"Biochem Biophys Res Commun"},{"key":"2024021014341580400_jbmr3378-bib-0042","doi-asserted-by":"crossref","first-page":"497","DOI":"10.1002\/jcp.21331","article-title":"Osteoclast stimulatory transmembrane protein (OC-STAMP), a novel protein induced by RANKL that promotes osteoclast differentiation","volume":"215","author":"Yang","year":"2008","journal-title":"J Cell Physiol"},{"issue":"5740","key":"2024021014341580400_jbmr3378-bib-0043","doi-asserted-by":"crossref","first-page":"1570","DOI":"10.1126\/science.1115901","article-title":"A strategy for probing the function of noncoding RNAs finds a repressor of NFAT","volume":"309","author":"Willingham","year":"2005","journal-title":"Science"},{"key":"2024021014341580400_jbmr3378-bib-0044","doi-asserted-by":"crossref","first-page":"11381","DOI":"10.1073\/pnas.1019711108","article-title":"Dephosphorylation of the nuclear factor of activated T cells (NFAT) transcription factor is regulated by an RNA-protein scaffold complex","volume":"108","author":"Sharma","year":"2011","journal-title":"Proc Natl Acad Sci U S A"},{"key":"2024021014341580400_jbmr3378-bib-0045","doi-asserted-by":"crossref","first-page":"181","DOI":"10.1016\/j.bone.2014.12.010","article-title":"The elementary fusion modalities of osteoclasts","volume":"73","author":"S\u00f8e","year":"2015","journal-title":"Bone"},{"issue":"12","key":"2024021014341580400_jbmr3378-bib-0046","doi-asserted-by":"crossref","first-page":"212","DOI":"10.5312\/wjo.v3.i12.212","article-title":"Osteoclast fusion and regulation by RANKL-dependent and independent factors","volume":"3","author":"Xing","year":"2012","journal-title":"World J Orthop"},{"key":"2024021014341580400_jbmr3378-bib-0047","doi-asserted-by":"crossref","first-page":"456","DOI":"10.1359\/JBMR.051204","article-title":"Pharmacological sequestration of intra-cellular cholesterol in late endosomes disrupts ruffled border formation in osteoclasts","volume":"21","author":"Zhao","year":"2006","journal-title":"J Bone Miner Res"},{"issue":"10","key":"2024021014341580400_jbmr3378-bib-0048","doi-asserted-by":"crossref","first-page":"1307","DOI":"10.1111\/j.1600-0854.2012.01395.x","article-title":"Membrane trafficking in osteoblasts and osteoclasts: new avenues for understanding and treating skeletal diseases","volume":"13","author":"Zhao","year":"2012","journal-title":"Traffic"}],"container-title":["Journal of Bone and Mineral Research"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.wiley.com\/onlinelibrary\/tdm\/v1\/articles\/10.1002%2Fjbmr.3378","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/academic.oup.com\/jbmr\/article-pdf\/33\/5\/888\/56651450\/jbmr3378.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/jbmr\/article-pdf\/33\/5\/888\/56651450\/jbmr3378.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,3,13]],"date-time":"2024-03-13T15:01:01Z","timestamp":1710342061000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/jbmr\/article\/33\/5\/888-898\/7605456"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2018,1,3]]},"references-count":48,"journal-issue":{"issue":"5","published-online":{"date-parts":[[2018,1,3]]},"published-print":{"date-parts":[[2018,5,1]]}},"URL":"https:\/\/doi.org\/10.1002\/jbmr.3378","relation":{},"ISSN":["0884-0431","1523-4681"],"issn-type":[{"value":"0884-0431","type":"print"},{"value":"1523-4681","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2018,5,1]]},"published":{"date-parts":[[2018,1,3]]}}}