RANK ligand-induced elevation of cytosolic Ca2+ accelerates nuclear translocation of nuclear factor κB in osteoclasts

被引:76
作者
Komarova, SV
Pilkington, MF
Weidema, AF
Dixon, SJ
Sims, SM [1 ]
机构
[1] Univ Western Ontario, Dept Physiol & Pharmacol, Fac Med & Dent, Div Oral Biol, London, ON N6A 5C1, Canada
[2] Univ Western Ontario, Dept Physiol & Pharmacol, CIHR Grp Skeletal Dev & Remodeling, London, ON N6A 5C1, Canada
关键词
D O I
10.1074/jbc.M206421200
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
PLANK ligand (RANKL) induces activation of NFkappaB, enhancing the formation, resorptive activity, and survival of osteoclasts. Ca2+ transduces many signaling events, however, it is not known whether the actions of RANKL involve Ca2+ signaling. We investigated the effects of RANKL on rat osteoclasts using microspectrofluorimetry and patch clamp. RANKL induced transient elevation of cytosolic free Ca2+ concentration ([Ca2+](i)) to maxima 220 nm above basal, resulting in activation of Ca2+-dependent K+ current. PANEL elevated [Ca2+](i) in Ca2+-containing and Ca2+-free media, and responses were prevented by the phospholipase C inhibitor U73122. Suppression of [Ca2+](i) elevation using the intracellular Ca2+ chelator 1,2-bis(O-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid (BAPTA) abolished the ability of RANKL to enhance osteoclast survival. Using immunofluorescence, NFkappaB was found predominantly in the cytosol of untreated osteoclasts. RANKL induced transient translocation of NFkappaB to the nuclei, which was maximal at 15 min. U73122 or BAPTA delayed nuclear translocation of NFkappaB. Delays were also observed upon inhibition of calcineurin or protein kinase C. We conclude that RANKL acts through phospholipase C to release Ca2+ from intracellular stores, accelerating nuclear translocation of NFkappaB and promoting osteoclast survival. Such cross-talk between NFkappaB and Ca2+ signaling provides a novel mechanism for the temporal regulation of gene expression in osteoclasts and other cell types.
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页码:8286 / 8293
页数:8
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