{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,28]],"date-time":"2026-09-28T21:24:03Z","timestamp":1790630643685,"version":"4.1.0"},"reference-count":37,"publisher":"The Company of Biologists","license":[{"start":{"date-parts":[[2012,12,15]],"date-time":"2012-12-15T00:00:00Z","timestamp":1355529600000},"content-version":"vor","delay-in-days":349,"URL":"http:\/\/www.biologists.com\/user-licence-1-1"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"abstract":"<jats:p>c-Fos plays essential roles in the osteoclastic differentiation of precursors generated by colony-stimulating factor 1 (CSF-1) and receptor activator of NF-\u03baB ligand (RANKL). RANKL-deficient (RANKL\u2212\/\u2212) mice and c-Fos\u2212\/\u2212 mice exhibit osteopetrosis due to an osteoclast deficiency. We previously reported that RANK-positive osteoclast precursors existed in bone in RANKL\u2212\/\u2212 mice but not c-Fos\u2212\/\u2212 mice. Here we examined the role of c-Fos in RANK expression in osteoclast precursors. Medullary thymic epithelial cells and intestinal antigen-sampling microfold cells have been shown to express RANK. High expression of RANK was observed in some epithelial cells in the thymic medulla and intestine but not in osteoclast precursors in c-Fos\u2212\/\u2212 mice. RANK mRNA and protein levels in bone were lower in c-Fos\u2212\/\u2212 mice than RANKL\u2212\/\u2212 mice, suggesting that c-Fos-regulated RANK expression is tissue specific. When wild-type bone marrow cells were inoculated into c-Fos\u2212\/\u2212 mice, RANK-positive cells appeared along bones. RANK expression in wild-type macrophages was up-regulated by coculturing with RANKL\u2212\/\u2212 osteoblasts as well as wild-type osteoblasts, suggesting that cytokines other than RANKL expressed by osteoblasts up-regulate RANK expression in osteoclast precursors. CSF-1 receptor-positive cells were detected near CSF-1-expressing osteoblastic cells in bone in c-Fos\u2212\/\u2212 mice. CSF-1 up-regulated RANK expression in wild-type macrophages but not c-Fos\u2212\/\u2212 macrophages. Overexpression of c-Fos in c-Fos\u2212\/\u2212 macrophages resulted in the up-regulation of RANK expression. Overexpression of RANK in c-Fos\u2212\/\u2212 macrophages caused RANKL-induced signals, but failed to recover the RANKL-induced osteoclastogenesis. These results suggest that c-Fos plays essential roles in the up-regulation of RANK expression in osteoclast precursors within the bone environment.<\/jats:p>","DOI":"10.1242\/jcs.099986","type":"journal-article","created":{"date-parts":[[2012,3,28]],"date-time":"2012-03-28T01:33:28Z","timestamp":1332898408000},"source":"Crossref","is-referenced-by-count":49,"title":["c-Fos plays an essential role in the up-regulation of RANK expression in osteoclast precursors within the bone microenvironment"],"prefix":"10.1242","author":[{"given":"Atsushi","family":"Arai","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Toshihide","family":"Mizoguchi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Suguru","family":"Harada","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yasuhiro","family":"Kobayashi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuko","family":"Nakamichi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hisataka","family":"Yasuda","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Josef M.","family":"Penninger","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kazuhiro","family":"Yamada","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nobuyuki","family":"Udagawa","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Naoyuki","family":"Takahashi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"237","published-online":{"date-parts":[[2012,1,1]]},"reference":[{"key":"2021042521511564900_b1","doi-asserted-by":"publisher","first-page":"423","DOI":"10.1016\/j.immuni.2008.06.015","article-title":"The tumor necrosis factor family receptors RANK and CD40 cooperatively establish the thymic medullary microenvironment and self-tolerance.","volume":"29","author":"Akiyama","year":"2008","journal-title":"Immunity"},{"key":"2021042521511564900_b2","doi-asserted-by":"publisher","first-page":"1741","DOI":"10.1084\/jem.190.12.1741","article-title":"Commitment and differentiation of osteoclast precursor cells by the sequential expression of c-Fms and receptor activator of nuclear factor kappaB (RANK) receptors.","volume":"190","author":"Arai","year":"1999","journal-title":"J. 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