Molecules and signaling pathways involved in the expression of OC-STAMP during osteoclastogenesis
Molecules and signaling pathways involved in the expression of OC-STAMP during osteoclastogenesis
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DOI：
10.1007/s00726-010-0755-4
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发表时间：
2011-05-01
期刊：
影响因子：
3.5
通讯作者：
Kim, Seong Hwan
中科院分区：
文献类型：
--
作者：
Kim, Myung Hee;Park, Mikyung;Kim, Seong Hwan
核因子-κ B配体受体激活因子（RANKL）是调节破骨细胞生成和维持成熟破骨细胞存活的关键因子。我们筛选了RAW264.7细胞对RANKL反应的差异表达基因，发现破骨细胞刺激跨膜蛋白（OC-STAMP）是RANKL诱导的感兴趣基因之一。最近，OC-STAMP已被鉴定为RANKL诱导的促进破骨细胞分化的蛋白，但调节其表达的机制尚不清楚。因此，在这里，OC-STAMP的组织分布和调节其表达的信号通路进行了研究。与破骨细胞相似，OC-STAMP在大多数组织中表达，表明其参与其他组织的功能。有趣的是，OC-STAMP在高浓度下被17 β-雌二醇下调，表明OC-STAMP和雌激素之间的潜在关系。重要的是，在转录水平敲低OC-STAMP导致多核破骨细胞形成的抑制和包括转录因子在内的基因表达的降低。（如c-Jun），受体（如RANK和c-Fms），信号分子（如TRAF 6）和细胞融合相关分子（如meltrin-alpha），表明破骨细胞分化需要OC-STAMP与转录、信号转导和细胞融合所需的几种分子的协调表达。此外，其特异性抗体的处理抑制了成熟破骨细胞的形成和骨吸收活性，表明其参与了成熟破骨细胞的功能。此外，药理学抑制剂的研究表明，PKC β或Akt可能是调节破骨细胞生成过程中OC-STAMP表达的主要信号分子。
The receptor activator of nuclear factor-kappa B ligand (RANKL) is a key factor in regulating osteoclastogenesis and in maintaining the survival of mature osteoclasts. We screened differentially expressed genes in RAW264.7 cells in response to RANKL and found osteoclast stimulatory transmembrane protein (OC-STAMP) as one of the RANKL-induced genes of interest. Recently, OC-STAMP has been identified as the RANKL-induced protein that promotes osteoclast differentiation, but the mechanism that regulates its expression is not understood. Therefore, the tissue distribution of OC-STAMP and the signaling pathways that regulate its expression were studied here. Similar to osteoclasts, OC-STAMP was expressed in most tissues, suggesting its involvement in the function of other tissues. Interestingly, OC-STAMP was downregulated by 17 beta-estradiol at high concentrations, suggesting the potential relationship between OC-STAMP and estrogen. Importantly, the knockdown of OC-STAMP at the transcript level resulted in the inhibition of multinucleated osteoclast formation and the decreased expression of genes including transcription factor (such as c-Jun), receptors (such as RANK and c-Fms), a signaling molecule (such as TRAF6), and a cell fusion-related molecule (such as meltrin-alpha), suggesting that the osteoclast differentiation needs the coordinated expression of OC-STAMP with several molecules required for transcription, signaling transduction, and cell fusion. Additionally, the treatment of its specific antibody inhibited the formation and bone resorptive activity of mature osteoclasts, suggesting its involvement in the function of mature osteoclasts. Furthermore, studies with pharmacological inhibitors suggested PKC beta or Akt might be the major signaling molecules to regulate the expression of OC-STAMP during osteoclastogenesis.