ST5 Positively Regulates Osteoclastogenesis via Src/Syk/Calcium Signaling Pathways
ST5 Positively Regulates Osteoclastogenesis via Src/Syk/Calcium Signaling Pathways
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DOI：
10.14348/molcells.2019.0189
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发表时间：
2019-11-01
影响因子：
3.8
通讯作者：
Kim, Hong-Hee
中科院分区：
文献类型：
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作者：
Kim, Min Kyung;Kim, Bongjun;Kim, Hong-Hee
为了从生理学或病理学上了解破骨细胞（OCs）异常行为引起的骨疾病，需要对调控OCs产生和作用的分子进行功能研究。在微阵列方法中，我们发现抑制致瘤性5（ST 5）基因被核因子-κ B配体受体激活因子（RANKL），OC分化因子上调。尽管已经报道了ST 5在癌症和β细胞中的作用，但尚未研究ST 5在骨细胞中的功能。通过siRNA敲低ST 5减少了OC从初级前体的分化。此外，ST 5下调降低了NFATc 1的表达，NFATc 1是破骨细胞生成的关键转录因子。相反，ST 5的过表达导致ST 5敲低的相反表型。在免疫细胞化学实验中，ST 5蛋白与Src在RANKL定向细胞中共定位。此外，ST 5增强了Src和Syk（Src底物）对RANKL的响应。ST 5减少导致RANKL诱发的钙振荡减少，并抑制NFATc 1易位到核中。总之，这些发现提供了第一个证据表明ST 5参与通过Src/Syk/钙信号传导的破骨细胞生成的正调控。
For physiological or pathological understanding of bone disease caused by abnormal behavior of osteoclasts (OCs), functional studies of molecules that regulate the generation and action of OCs are required. In a microarray approach, we found the suppression of tumorigenicity 5 (ST5) gene is upregulated by receptor activator of nuclear factor-kappa B ligand (RANKL), the OC differentiation factor. Although the roles of ST5 in cancer and beta-cells have been reported, the function of ST5 in bone cells has not yet been investigated. Knockdown of ST5 by siRNA reduced OC differentiation from primary precursors. Moreover, ST5 downregulation decreased expression of NFATc1, a key transcription factor for osteoclastogenesis. In contrast, overexpression of ST5 resulted in the opposite phenotype of ST5 knockdown. In immunocytochemistry experiments, the ST5 protein is colocalized with Src in RANKL-committed cells. In addition, ST5 enhanced activation of Src and Syk, a Src substrate, in response to RANKL. ST5 reduction caused a decrease in RANKL-evoked calcium oscillation and inhibited translocation of NFATc1 into the nucleus. Taken together, these findings provide the first evidence of ST5 involvement in positive regulation of osteoclastogenesis via Src/Syk/calcium signaling.