12-O-tetradecanoylphorbol-13-acetate (TPA) inhibits osteoclastogenesis by suppressing RANKL-induced NF-κB activation

被引:131
作者
Wang, C
Steer, JH
Joyce, DA
Yip, KHM
Zheng, MH
Xu, J
机构
[1] Univ Western Australia, Sch Surg & Pathol, Dept Orthopaed, QEII Med Ctr, Nedlands, WA 6009, Australia
[2] Univ Western Australia, Dept Pharmacol, Nedlands, WA 6009, Australia
关键词
RANKL; osteoclastogenesis; 12-o-tetradecanoylphorbol-13-acetate; protein kinase C; NF-kappa B;
D O I
10.1359/jbmr.2003.18.12.2159
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
Introduction: The protein kinase C (PKC) pathway has been suggested to be an important regulator of osteoclastic bone resorption. The role of PKC in RANKL-induccd osteoclastogenesis, however, is not clear. In this study, we examined the effects of 12-O-tetradecanoylphorbol-13-acetate (TPA), a PKC activator, on osteoclastogenesis and studied its role in RANKL-induced signaling. Materials and Methods: RANKL-induced RAW(264.7) cell differentiation into osteoclast-like cells was used to assess the effect of TPA on osteoclastogenesis. Assays for NF-kappaB nuclear translocation, NF-kappaB reporter gene activity, protein kinase activity, and Western blotting were used to examine the effects of TPA on RANKL-induced NF-kappaB, c-Jun N-terminal kinase (INK), and MEK/ERK and p38 signal transduction pathways. Results: We found that TPA inhibited RANKL-induced RAW264.7 cell differentiation into osteoclasts in a dose-dependent manner. Time course analysis showed that the inhibitory effect of TPA on RANKL-induced osteoclastogenesis occurs predominantly at an early stage of osteoclast differentiation. TPA alone had little effect on NF-kappaB activation in RAW264.7 cells, but it suppresses the RANKL-induced NF-kappaB activation in a dose-dependent fashion. Interestingly, the suppressive effect of TPA on RANKL-induced NF-kappaB activation was prevented by a conventional PKC inhibitor, Go6976. Supershift studies revealed that the RANKL-induced DNA binding of NF-kappaB complexes consisted of C-Rel, NF-kappaB1 (p50), and RelA (p65). In addition, TPA induced the activation of JNK in RAW(264.7) cells but had little effect on RANKL-induced activation of JNK. TPA also inhibited RANKL-induced activation of ERK but had little effect on p38 activation. Conclusion: Given that NF-kappaB activation is obligatory for osteoclast differentiation, our studies imply that inhibition of osteoclastogenesis by TPA is, at least in part, caused by the suppression of RANKL-induced activation of NF-kappaB during an early stage of osteoclastogenesis. Selective modulation of RANKL signaling pathways by PKC activators may have important therapeutic implications for the treatment of bone diseases associated with enhanced bone resorption.
引用
收藏
页码:2159 / 2168
页数:10
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