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CCAAT\/enhancer\u2010binding protein \u03b1 (C\/ebp\u03b1) has been reported to be a key regulator of osteoclast cell lineage commitment, yet C\/ebp\u03b1's roles in osteoclast terminal differentiation, activation and function, and bone homeostasis, under physiological or pathological conditions, have not been studied because newborn C\/ebp\u03b1\u2010null mice die within several hours after birth. Furthermore, the function of <jats:italic>C\/ebp\u03b1<\/jats:italic> in osteoclast terminal differentiation, activation, and function is largely unknown. Herein, we generated and analyzed an osteoclast\u2010specific <jats:italic>C\/ebp\u03b1<\/jats:italic> conditional knockout (CKO) mouse model via <jats:italic>Ctsk\u2010Cre<\/jats:italic> mice and found that C\/ebp\u03b1\u2010deficient mice exhibited a severe osteopetrosis phenotype due to impaired osteoclast terminal differentiation, activation, and function, including mildly reduced osteoclast number, impaired osteoclast polarization, actin formation, and bone resorption, which demonstrated the novel function of C\/ebp\u03b1 in cell function and terminal differentiation. Interestingly, C\/ebp\u03b1 deficiency did not affect bone formation or monocyte\/macrophage development. Our results further demonstrated that C\/ebp\u03b1 deficiency suppressed the expression of osteoclast functional genes, e.g. encoding cathepsin K (<jats:italic>Ctsk<\/jats:italic>), Atp6i (<jats:italic>Tcirg1<\/jats:italic>), and osteoclast regulator genes, e.g. encoding c\u2010fos (<jats:italic>Fos<\/jats:italic>), and nuclear factor of activated T\u2010cells 1 (<jats:italic>Nfatc1<\/jats:italic>), while having no effect on Pu.1 (<jats:italic>Spi1<\/jats:italic>) expression. Promoter activity mapping and ChIP assay defined the critical <jats:italic>cis<\/jats:italic>\u2010regulatory element (CCRE) in the promoter region of <jats:italic>Nfatc1<\/jats:italic>, and also showed that the CCREs were directly associated with C\/ebp\u03b1, which enhanced the promoter's activity. The deficiency of C\/ebp\u03b1 in osteoclasts completely blocked ovariectomy\u2010induced bone loss, indicating that C\/ebp\u03b1 is a promising new target for the treatment of osteolytic diseases. Copyright \u00a9 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley &amp; Sons, Ltd.<\/jats:p>","DOI":"10.1002\/path.5001","type":"journal-article","created":{"date-parts":[[2017,10,30]],"date-time":"2017-10-30T08:48:42Z","timestamp":1509353322000},"page":"271-282","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":23,"title":["C\/ebp\u03b1 controls osteoclast terminal differentiation, activation, function, and postnatal bone homeostasis through direct regulation of Nfatc1"],"prefix":"10.1002","volume":"244","author":[{"given":"Wei","family":"Chen","sequence":"first","affiliation":[{"name":"Department of Pathology University of Alabama at Birmingham School of Medicine  Birmingham Alabama USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guochun","family":"Zhu","sequence":"additional","affiliation":[{"name":"Department of Pathology University of Alabama at Birmingham School of Medicine  Birmingham Alabama USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jun","family":"Tang","sequence":"additional","affiliation":[{"name":"Department of Pathology University of Alabama at Birmingham School of Medicine  Birmingham Alabama USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hou\u2010De","family":"Zhou","sequence":"additional","affiliation":[{"name":"Department of Metabolism and Endocrinology, National Clinical Research Center for Metabolic Diseases, The Second Xiangya Hospital Central South University  ChangSha Hunan PR China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2188-6958","authenticated-orcid":false,"given":"Yi\u2010Ping","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Pathology University of Alabama at Birmingham School of Medicine  Birmingham Alabama USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2018,1,29]]},"reference":[{"key":"e_1_2_7_2_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature01658"},{"key":"e_1_2_7_3_1","first-page":"1","article-title":"Signaling networks that control the lineage commitment and differentiation of bone cells. 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