• Made available online as an Accepted Preprint 4 June 2010
  • Accepted Preprint first posted online on 4 June 2010

Insulin receptor substrate 1 regulates the cellular differentiation and the matrix metallopeptidase expression of preosteoblastic cells

  1. Er-Yuan Liao1
  1. 1Institute of Metabolism and Endocrinology
    2Department of Clinical Laboratory
    3Department of Orthopaedics, The Second Xiang-Ya Hospital of Central South University, 410011 ChangSha, People's Republic of China
  1. (Correspondence should be addressed to H-D Zhou; Email: houdezhou{at}xysm.net)


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.

  • Received in final form 23 May 2010
  • Accepted 4 June 2010
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