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Shp2 (the Src homology\u20102 domain containing protein tyrosine phosphatase 2), a ubiquitously expressed cytoplasmic protein tyrosine phosphatase, is implicated in regulating M\u2010CSF and receptor activator of nuclear factor\u2010\u03baB ligand (RANKL)\u2010 evoked signaling; its role in osteoclastogenesis and bone homeostasis, however, remains unknown. Using a tissue\u2010specific gene knockout approach, we inactivated Shp2 expression in murine OCs. Shp2 mutant mice are phenotypically osteopetrotic, featuring a marked increase of bone volume (BV)\/total volume (TV) (+42.8%), trabeculae number (Tb.N) (+84.1%), structure model index (+119%), and a decrease of trabecular thickness (Tb.Th) (\u201034.1%) and trabecular spacing (Tb.Sp) (\u201041.0%). Biochemical analyses demonstrate that Shp2 is required for RANKL\u2010induced formation of giant multinucleated OCs by up\u2010regulating the expression of nuclear factor of activated T cells, cytoplasmic 1 (Nfatc1), a master transcription factor that is indispensable for terminal OC differentiation. Shp2 deletion, however, has minimal effect on M\u2010CSF\u2010dependent survival and proliferation of OC precursors. Instead, its deficiency aborts the fusion of OC precursors and formation of multinucleated OCs and decreases bone matrix resorption. Moreover, pharmacological intervention of Shp2 is sufficient to prevent preosteoclast fusion\n                    <jats:italic>in vitro.<\/jats:italic>\n                    These findings uncover a novel mechanism through which Shp2 regulates osteoclastogenesis by promoting preosteoclast fusion. Shp2 or its signaling partners could potentially serve as pharmacological targets to regulate the population of OCs locally and\/or systematically, and thus treat OC\u2010related diseases, such as periprosthetic osteolysis and osteoporosis.\u2014Zhou, Y., Mohan, A., Moore, D. C., Lin, L., Zhou, F. L., Cao, J., Wu, Q., Qin, Y.\u2010X., Reginato, A. M., Ehrlich, M. G., Yang, W. SHP2 regulates osteoclastogenesis by promoting preosteoclast fusion.\n                    <jats:italic>FASEB J.<\/jats:italic>\n                    29, 1635\u20101645 (2015).\n                    <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" xlink:href=\"http:\/\/www.fasebj.org\">www.fasebj.org<\/jats:ext-link>\n                  <\/jats:p>","DOI":"10.1096\/fj.14-260844","type":"journal-article","created":{"date-parts":[[2015,1,15]],"date-time":"2015-01-15T22:01:28Z","timestamp":1421359288000},"page":"1635-1645","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":35,"title":["SHP2 regulates osteoclastogenesis by promoting preosteoclast fusion"],"prefix":"10.1096","volume":"29","author":[{"given":"Yi","family":"Zhou","sequence":"first","affiliation":[{"name":"Stem Cell Program Boston Children's Hospital and Harvard Medical School Boston Massachusetts USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aron","family":"Mohan","sequence":"additional","affiliation":[{"name":"Department of Orthopaedics Brown University Alpert Medical School and Rhode Island Hospital Providence Rhode Island USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Douglas C.","family":"Moore","sequence":"additional","affiliation":[{"name":"Department of Orthopaedics Brown University Alpert Medical School and Rhode Island Hospital Providence Rhode Island USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Liangjun","family":"Lin","sequence":"additional","affiliation":[{"name":"Department of Biomedical Engineering State University of New York at Stony Brook Stony Brook New York USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Frank Li","family":"Zhou","sequence":"additional","affiliation":[{"name":"Engineering and Applied Science California Institute of Technology Pasadena California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jay","family":"Cao","sequence":"additional","affiliation":[{"name":"U.S. Department of Agriculture Grand Forks Human Nutrition Research Center Grand Forks North Dakota USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qian","family":"Wu","sequence":"additional","affiliation":[{"name":"Department of Pathology and Laboratory Medicine University of Connecticut Health Center Farmington Connecticut USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yi\u2010Xian","family":"Qin","sequence":"additional","affiliation":[{"name":"Department of Biomedical Engineering State University of New York at Stony Brook Stony Brook New York USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anthony M.","family":"Reginato","sequence":"additional","affiliation":[{"name":"Division of Rheumatology Brown University Alpert Medical School and Rhode Island Hospital Providence Rhode Island USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael G.","family":"Ehrlich","sequence":"additional","affiliation":[{"name":"Department of Orthopaedics Brown University Alpert Medical School and Rhode Island Hospital Providence Rhode Island USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wentian","family":"Yang","sequence":"additional","affiliation":[{"name":"Department of Orthopaedics Brown University Alpert Medical School and Rhode Island Hospital Providence Rhode Island USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2015,1,15]]},"reference":[{"key":"e_1_2_7_2_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.289.5484.1504"},{"key":"e_1_2_7_3_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature01658"},{"key":"e_1_2_7_4_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.molmed.2005.11.007"},{"key":"e_1_2_7_5_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrg1122"},{"key":"e_1_2_7_6_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bone.2006.09.023"},{"key":"e_1_2_7_7_1","doi-asserted-by":"publisher","DOI":"10.1196\/annals.1346.014"},{"key":"e_1_2_7_8_1","doi-asserted-by":"publisher","DOI":"10.1016\/S1534-5807(02)00369-6"},{"key":"e_1_2_7_9_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M109.001016"},{"key":"e_1_2_7_10_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.gene.2009.06.013"},{"key":"e_1_2_7_11_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.yexcr.2006.10.001"},{"key":"e_1_2_7_12_1","doi-asserted-by":"publisher","DOI":"10.1210\/me.2007-0237"},{"key":"e_1_2_7_13_1","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20050645"},{"key":"e_1_2_7_14_1","first-page":"771","volume-title":"Handbook of Cell Signaling","author":"Neel B. 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