{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,13]],"date-time":"2026-09-13T11:34:39Z","timestamp":1789299279617,"version":"build-2803163510"},"reference-count":24,"publisher":"National Academy of Sciences","issue":"18","content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2013,4,30]]},"abstract":"\n Despite recent insights gained from the effects of targeted deletion of the\n Finkel-Biskis-Jinkins osteosarcoma oncogene (c-fos)<\/jats:italic>\n ,\n Spleen focus-forming virus<\/jats:italic>\n (\n SFFV<\/jats:italic>\n )\n proviral integration 1 (PU.1)<\/jats:italic>\n ,\n microphthalmia-associated transcription factor<\/jats:italic>\n ,\n NF-\u03baB<\/jats:italic>\n , and\n nuclear factor of activated cells cytoplasmic 1<\/jats:italic>\n (\n NFATc1<\/jats:italic>\n ) transcription factor genes, the mechanism underlying transcription factors specifying osteoclast (OC) lineage commitment from monocyte\/macrophage remains unclear. To characterize the mechanism by which transcription factors regulate OC lineage commitment, we mapped the critical\n cis<\/jats:italic>\n -regulatory element in the promoter of\n cathepsin K<\/jats:italic>\n (\n Ctsk<\/jats:italic>\n ), which is expressed specifically in OCs, and found that CCAAT\/enhancer binding protein \u03b1 (C\/EBP\u03b1) is the critical\n cis<\/jats:italic>\n -regulatory element binding protein. Our results indicate that C\/EBP\u03b1 is highly expressed in pre- OCs and OCs. The combined presence of macrophage colony-stimulating factor and receptor activator of NF-\u03baB ligand significantly induces high C\/EBP\u03b1 expression. Furthermore,\n C\/EBP\u03b1<\/jats:italic>\n \u2212\/\u2212<\/jats:sup>\n newborn mice exhibited impaired osteoclastogenesis, and a severe osteopetrotic phenotype, but unaffected monocyte\/macrophage development. Impaired osteoclastogenesis of\n C\/EBP\u03b1<\/jats:italic>\n \u2212\/\u2212<\/jats:sup>\n mouse bone marrow cells can be rescued by\n c-fos<\/jats:italic>\n overexpression. Ectopic expression of C\/EBP\u03b1 in mouse bone marrow cells and monocyte\/macrophage cells, in the absence of receptor activator of NF-\u03baB ligand, induces expression of\n receptor activator of NF-\u03baB, c-fos, Nfatc1<\/jats:italic>\n , and\n Ctsk<\/jats:italic>\n , and it reprograms monocyte\/macrophage cells to OC-like cells. Our results demonstrate that C\/EBP\u03b1 directly up-regulates\n c-fos<\/jats:italic>\n expression. C\/EBP\u03b1\n +\/\u2212<\/jats:sup>\n mice exhibit an increase in bone density compared with C\/EBP\u03b1\n +\/+<\/jats:sup>\n controls. These discoveries establish C\/EBP\u03b1 as the key transcriptional regulator of OC lineage commitment, providing a unique therapeutic target for diseases of excessive bone resorption, such as osteoporosis and arthritis.\n <\/jats:p>","DOI":"10.1073\/pnas.1211383110","type":"journal-article","created":{"date-parts":[[2013,4,11]],"date-time":"2013-04-11T23:53:13Z","timestamp":1365724393000},"page":"7294-7299","update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":74,"title":["C\/EBP\u03b1 regulates osteoclast lineage commitment"],"prefix":"10.1073","volume":"110","author":[{"given":"Wei","family":"Chen","sequence":"first","affiliation":[{"name":"Department of Pathology, University of Alabama at Birmingham, Birmingham, AL 35294-2182"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guochun","family":"Zhu","sequence":"additional","affiliation":[{"name":"Department of Pathology, University of Alabama at Birmingham, Birmingham, AL 35294-2182"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Liang","family":"Hao","sequence":"additional","affiliation":[{"name":"Department of Pathology, University of Alabama at Birmingham, Birmingham, AL 35294-2182"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mengrui","family":"Wu","sequence":"additional","affiliation":[{"name":"Department of Pathology, University of Alabama at Birmingham, Birmingham, AL 35294-2182"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hongliang","family":"Ci","sequence":"additional","affiliation":[{"name":"Department of Pathology, University of Alabama at Birmingham, Birmingham, AL 35294-2182"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yi-Ping","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Pathology, University of Alabama at Birmingham, Birmingham, AL 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