Insulin receptor substrate-1 time-dependently regulates bone formation by controlling collagen Iα2 expression via miR-342.
Insulin receptor substrate-1 time-dependently regulates bone formation by controlling collagen Iα2 expression via miR-342.
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胰岛素受体底物 1 通过 miR-342 控制胶原蛋白 I α 2 表达，时间依赖性地调节骨形成
DOI：
10.1096/fj.201600445rr
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发表时间：
2016-12
期刊：
影响因子：
--
通讯作者：
Zhou HD
中科院分区：
文献类型：
--
作者：
Guo Y;Tang CY;Man XF;Tang HN;Tang J;Wang F;Zhou CL;Tan SW;Feng YZ;Zhou HD
胰岛素通过一个研究充分的经典信号通路促进骨形成。胰岛素受体底物（IRS）-1是这一通路中的一个接头，它与胰岛素信号传导受损引起的糖尿病性骨病有关。为了进一步研究IRS-1在骨代谢中的作用，我们产生了IRS-1缺陷型Irs-1smla/smla小鼠。这些无效小鼠自发突变，导致增加骨小梁厚度（Tb. Th）在12月龄，但不是在2月龄小鼠。对这些小鼠的骨髓基质细胞（BMSCs）的分析揭示了它们成骨相关基因和miRNA的差异表达。miR-342的表达，预测，然后证明靶向编码胶原蛋白I型α 2（COL1A2）的基因，在来源于Irs-1-null小鼠的BMSC中减少。然后显示，在来源于Irs-1smla/smla小鼠的成骨细胞和BMSC中，COL1A2表达具有年龄依赖性。在诱导BMSCs成骨后，miR-342的表达与Col1a2的表达呈负相关。此外，Col1a2特异性小干扰RNA（siRNA）降低碱性磷酸酶（ALP）活性，抑制BMSC分化为骨细胞样细胞，在野生型（WT）和Irs-1smla/smla小鼠。相反，在过表达COL1A2的Irs-1smla/smla骨细胞中，ALP阳性染色强于WT骨细胞。总之，我们发现了BMSC分化/骨形成的时间调节，通过Irs-1/miR-342介导的Col1a2表达调节来控制。Guo，Y.，中国科学院，唐角，澳-地是的，伙计，X。- F.、唐，H. - N.，唐，J.，王福，周氏C. L.，谭，S. - W.，冯玉-- Z.，周洪- D.胰岛素受体底物-1通过miR-342控制胶原I α 2表达，以时间依赖性方式调节骨形成。
Insulin promotes bone formation via a well-studied canonical signaling pathway. An adapter in this pathway, insulin-receptor substrate (IRS)-1, has been implicated in the diabetic osteopathy provoked by impaired insulin signaling. To further investigate IRS-1’s role in the bone metabolism, we generated Irs-1-deficient Irs-1smla/smla mice. These null mice developed a spontaneous mutation that led to an increase in trabecular thickness (Tb.Th) in 12-mo-old, but not in 2-mo-old mice. Analyses of the bone marrow stromal cells (BMSCs) from these mice revealed their differential expression of osteogenesis-related genes and miRNAs. The expression of miR-342, predicted and then proven to target the gene encoding collagen type Iα2 (COL1A2), was reduced in BMSCs derived from Irs-1-null mice. COL1A2 expression was then shown to be age dependent in osteoblasts and BMSCs derived from Irs-1smla/smla mice. After the induction of osteogenesis in BMSCs, miR-342 expression correlated inversely with that of Col1a2. Further, Col1a2-specific small interfering RNA (siRNA) reduced alkaline phosphatase (ALP) activity and inhibited BMSC differentiation into osteocyte-like cells, both in wild-type (WT) and Irs-1smla/smla mice. Conversely, in Irs-1smla/smla osteocytes overexpressing COL1A2, ALP-positive staining was stronger than in WT osteocytes. In summary, we uncovered a temporal regulation of BMSC differentiation/bone formation, controlled via Irs-1/miR-342 mediated regulation of Col1a2 expression.—Guo, Y., Tang, C.-Y., Man, X.-F., Tang, H.-N., Tang, J., Wang, F., Zhou, C.-L., Tan, S.-W., Feng, Y.-Z., Zhou, H.-D. Insulin receptor substrate-1 time-dependently regulates bone formation by controlling collagen Iα2 expression via miR-342.