{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,4]],"date-time":"2026-10-04T04:48:50Z","timestamp":1791089330233,"version":"4.1.0"},"reference-count":22,"publisher":"Oxford University Press (OUP)","issue":"6","license":[{"start":{"date-parts":[[2008,6,1]],"date-time":"2008-06-01T00:00:00Z","timestamp":1212278400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/journals\/pages\/open_access\/funder_policies\/chorus\/standard_publication_model"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2008,6,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>Introduction: RANKL is known to be important not only for differentiation and activation of osteoclasts but also for their survival. Experimentally, apoptosis of osteoclasts is rapidly induced by the deprivation of RANKL. RANKL activates Elk-related tyrosine kinase (ERK), p38, c-Jun N-terminal kinase (JNK), and NF-\u03baB pathways through TRAF6 in osteoclasts and the precursor cells. It has been shown that ERK is critical for regulation of osteoclast survival. However, an involvement of other RANKL signaling pathways such as JNK signaling in survival of osteoclasts has not been fully understood yet.<\/jats:p>\n               <jats:p>Materials and Methods: Osteoclasts derived from primary mouse bone marrow cells by soluble RANKL (sRANKL) were treated with a JNK inhibitor, SP600125, or infected with adenovirus carrying dominant-negative (DN)-c-jun, DN-c-fos, mitogen-activated protein kinase kinase 1 (MEKK1), I-\u03baB\u03b1 mutant, or NF-\u03baB components, p50 and p65. Osteoclasts were cultured with or without sRANKL, and apoptotic phenotype was determined by TUNEL assay, DAPI staining, and expression of cleaved caspase 3 followed by TRACP staining.<\/jats:p>\n               <jats:p>Results: Overexpression of TRAF6 activated JNK and NF-\u03baB signaling pathways and clearly prevented osteoclasts from apoptosis caused by abrogation of sRANKL. An anti-apoptotic effect of RANKL\/RANK\/TRAF6 signaling on osteoclast was inhibited by JNK-specific inhibitor SP600125 and by overexpression of dominant-negative JNK1, c-jun, and c-fos. Also, overexpression of MEKK1 inhibited apoptosis of osteoclasts even in the absence of sRANKL along with activation of JNK\/c-jun signaling. On the other hand, blockade of NF-\u03baB signaling by I-\u03baB\u03b1 mutant or overexpression of NF-\u03baB components showed a marginal effect on apoptosis of osteoclasts.<\/jats:p>\n               <jats:p>Conclusions: An important role of RANKL-induced activation of MEKK1\/JNK\/c-jun signaling in the regulation of apoptosis in osteoclasts was shown. Our study suggests that c-fos plays a role as a partner of activator protein-1 factor, c-jun, during the regulation of apoptosis in osteoclasts.<\/jats:p>","DOI":"10.1359\/jbmr.080211","type":"journal-article","created":{"date-parts":[[2008,2,5]],"date-time":"2008-02-05T18:40:45Z","timestamp":1202236845000},"page":"907-914","source":"Crossref","is-referenced-by-count":120,"title":["JNK\/c-Jun Signaling Mediates an Anti-Apoptotic Effect of RANKL in Osteoclasts"],"prefix":"10.1093","volume":"23","author":[{"given":"Fumiyo","family":"Ikeda","sequence":"first","affiliation":[{"name":"Institute of Biochemistry II, Goethe University Medical School, Frankfurt, Germany"},{"name":"Department of Biochemistry, Osaka University Graduate School of Dentistry, Osaka, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takuma","family":"Matsubara","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, Osaka University Graduate School of Dentistry, Osaka, 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