Insulin receptor substrate 1 regulates the cellular differentiation and the matrix metallopeptidase expression of preosteoblastic cells
Insulin receptor substrate 1 regulates the cellular differentiation and the matrix metallopeptidase expression of preosteoblastic cells
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DOI：
10.1677/joe-10-0064
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发表时间：
2010-09-01
影响因子：
4
通讯作者：
Liao, Er-Yuan
中科院分区：
文献类型：
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作者：
Bu, Yan-Hong;He, Yu-Ling;Liao, Er-Yuan
胰岛素受体底物1 （IRS1）是IGF1和胰岛素细胞内信号转导的重要分子，IGF1和胰岛素是骨代谢的有效合成代谢调节剂。成骨细胞IRS1对维持骨转换至关重要；然而，这种监管的机制尚不清楚。为了明确IRS1在骨代谢中的作用，我们采用RNA干扰抑制IRS1基因表达，观察沉默该基因对MC3T3-E1细胞基质金属肽酶（MMP）和肿瘤坏死因子受体超家族成员11b （TNFRSF11B）增殖分化及表达的影响。我们的研究结果表明，IRS1短发夹rna可以有效抑制IRS1的表达，抑制IRS1通路中AKT的磷酸化；降低MMP2、MMP3、MMP13、MMP14的表达，降低TNFRSF11B和RANKL（又称肿瘤坏死因子（配体）超家族成员11）的表达，但增加RANKL/TNFRSF11B比值；降低MC3T3-E1细胞的存活、增殖和矿化，损害MC3T3-E1细胞的分化。IRS1的下调对MMP1的表达无影响。我们的研究结果表明，IRS1不仅促进骨形成和矿化，还可能通过调控MMPs和RANKL/TNFRSF11B的比例部分参与骨吸收，从而调控骨转换。内分泌学杂志（2010）206,271-277
Insulin receptor substrate 1 (IRS1) is an essential molecule for the intracellular signaling of IGF1 and insulin, which are potent anabolic regulators of bone metabolism. Osteoblastic IRS1 is essential for maintaining bone turnover; however, the mechanism underlying this regulation remains unclear. To clarify the role of IRS1 in bone metabolism, we employed RNA interference to inhibit IRS1 gene expression and observed the effects of silencing this gene on the proliferation and differentiation of and the expression of matrix metallopeptidase (MMP) and tumor necrosis factor receptor superfamily, member 11b (TNFRSF11B) in MC3T3-E1 cells. Our results showed that IRS1 short hairpin RNAs can effectively suppress the expression of IRS1, and inhibit the phosphorylation of AKT in IRS1 pathway; reduce the expression of MMP2, MMP3, MMP13, and MMP14, decrease the expression of TNFRSF11B and RANKL (also known as tumor necrosis factor (ligand) superfamily, member 11), however increase the RANKL/TNFRSF11B ratio; decrease cell survival, proliferation, and mineralization, and impair the differentiation of MC3T3-E1 cells. The downregulation of IRS1 had no effect on the expression of MMP1. Our findings suggest that IRS1 not only promotes bone formation and mineralization but also might play roles in bone resorption partly via the regulation of MMPs and RANKL/TNFRSF11B ratio, thus regulates the bone turnover. Journal of Endocrinology (2010) 206, 271-277