Insulin receptor substrate-1 time-dependently regulates bone formation by controlling collagen Iα2 expression via miR-342.
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/smlamice. 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/smlamice. 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/smlamice. Conversely, in Irs-1smla/smlaosteocytes 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.
Department of Endocrinology and Metabolism, National Clinical Research Center for Metabolic Disease, The Second Xiangya Hospital, Central South University, Changsha, Hunan, China; and.
Yue
Y
Guo
Department of Endocrinology and Metabolism, National Clinical Research Center for Metabolic Disease, The Second Xiangya Hospital, Central South University, Changsha, Hunan, China; and.
Chen-Yi
CY
Tang
Department of Endocrinology and Metabolism, National Clinical Research Center for Metabolic Disease, The Second Xiangya Hospital, Central South University, Changsha, Hunan, China; and.
Xiao-Fei
XF
Man
Department of Endocrinology and Metabolism, National Clinical Research Center for Metabolic Disease, The Second Xiangya Hospital, Central South University, Changsha, Hunan, China; and.
Hao-Neng
HN
Tang
Department of Endocrinology and Metabolism, National Clinical Research Center for Metabolic Disease, The Second Xiangya Hospital, Central South University, Changsha, Hunan, China; and.
Jun
J
Tang
Department of Endocrinology and Metabolism, National Clinical Research Center for Metabolic Disease, The Second Xiangya Hospital, Central South University, Changsha, Hunan, China; and.
Fang
F
Wang
Department of Endocrinology and Metabolism, National Clinical Research Center for Metabolic Disease, The Second Xiangya Hospital, Central South University, Changsha, Hunan, China; and.
Ci-La
CL
Zhou
Department of Endocrinology and Metabolism, National Clinical Research Center for Metabolic Disease, The Second Xiangya Hospital, Central South University, Changsha, Hunan, China; and.
Shu-Wen
SW
Tan
Department of Stomatology, The Second Xiangya Hospital, Central South University, Hunan, China.
Yun-Zhi
YZ
Feng
Department of Endocrinology and Metabolism, National Clinical Research Center for Metabolic Disease, The Second Xiangya Hospital, Central South University, Changsha, Hunan, China; and houdezhou@csu.edu.cn.
Hou-De
HD
Zhou
D000818:Animals; D001854:Bone Marrow Cells / Q000166:cytology*; D002454:Cell Differentiation / Q000502:physiology; D002478:Cells, Cultured; D024042:Collagen Type I / Q000235:genetics / Q000378:metabolism*; D055504:Insulin Receptor Substrate Proteins / Q000235:genetics / Q000378:metabolism*; D059630:Mesenchymal Stem Cells / Q000166:cytology*; D008822:Mice, Transgenic; D035683:MicroRNAs / Q000235:genetics*; D010006:Osteoblasts / Q000166:cytology; D010012:Osteogenesis / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology; D013997:Time Factors
C000619309:Col1a2 protein, mouse; D024042:Collagen Type I; D055504:Insulin Receptor Substrate Proteins; D035683:MicroRNAs; C581863:Mirn342 microRNA, mouse
bone formation; collagen 1α2; insulin receptor substrate; miR-342