Cobalt protoporphyrin represses osteoclastogenesis through blocking multiple signaling pathways
Cobalt protoporphyrin represses osteoclastogenesis through blocking multiple signaling pathways
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DOI：
10.1007/s10534-015-9861-9
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发表时间：
2015-05
期刊：
影响因子：
3.5
通讯作者：
Y. Yashima;K. Okamoto;E. Sakai;M. Iwatake;Yutaka Fukuma;K. Nishishita;T. Tsukuba
中科院分区：
文献类型：
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作者：
Y. Yashima;K. Okamoto;E. Sakai;M. Iwatake;Yutaka Fukuma;K. Nishishita;T. Tsukuba
钴原卟啉(CoPP)是一种金属原卟啉，在多种组织和细胞中都是血红素氧合酶-1(HO-1)的强大诱导剂。我们最近的研究表明，几种试剂诱导的HO-1抑制了破骨细胞(OCL)的分化和激活，破骨细胞是多核的骨吸收细胞。然而，CoPP在破骨细胞形成中的作用尚不清楚。在本研究中，我们报道了CoPP以剂量依赖的方式抑制核因子κB配体受体激活剂(RANKL)诱导的OCL的形成。重要的是，CoPP的细胞毒性很小，但却能促进OCL的细胞增殖。CoPP抑制成熟OCL中活化T细胞胞浆核因子-1(NFATc1)的蛋白水平，以及受NFATc1转录调控的OCLs标志物如Src和组织蛋白酶K的蛋白水平。Western印迹分析还显示，CoPP可阻断RANKL刺激的OCL前体细胞中IκB、Akt、ERK、JNK和p38MAPKs等几个主要信号通路的磷酸化。因此，我们的结果表明，CoPP通过阻断多个信号通路来抑制破骨细胞的形成。
Cobalt protoporphyrin (CoPP) is a metallo-protoporphyrin that works as a powerful inducer of heme oxigenase-1 (HO-1) in various tissues and cells. Our recent studies have demonstrated that induction of HO-1 by several reagents inhibited differentiation and activation of osteoclasts (OCLs), which are multinucleated bone resorbing cells. However, the effects of CoPP on osteoclastogenesis remain to be elucidated. In this study, we report that CoPP inhibits receptor activator of nuclear factor κB ligand (RANKL)-induced OCL formation in a dose dependent manner. Importantly, CoPP had little cytotoxicity, but rather enhanced cell proliferation of OCLs. CoPP suppressed the protein levels of nuclear factor of activated T cells cytoplasmic-1 (NFATc1) as well as those of OCLs markers such as Src and cathepsin K, which are transcriptionally regulated by NFATc1 in mature OCLs. Western blot analyses also showed that CoPP abolished RANKL-stimulated phosphorylation of several major signaling pathways such as IκB, Akt, ERK, JNK and p38 MAPKs in OCL precursor cells. Thus, our results show that CoPP represses osteoclastogenesis through blocking multiple signaling pathways.