Insulin receptor substrate‐1 time‐dependently regulates bone formation by controlling collagen Iα2 expression via miR‐342

Abstract

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.

Studying hepcidin and related pathways in osteoblasts using a mouse model with insulin receptor substrate 1‑loss of function

“…In the present study, the protein expression levels of BMPR1α were significantly elevated within IRS -/mice, in accordance with the data obtained via microRNA and PCR arrays in a previous study (37). In order to further understand the role of the BMP signaling pathway in hepcidin expression within IRS -/mice, the mRNA expression level of BMP6 was studied via RT-qPCR analyses.…”

“…A mutation of the 57th amino acid of this protein led to the disappearance of its expression. In a previous preliminary study, it was demonstrated that these IRS -/mice manifested osteogenesis imperfecta and adipogenesis imperfecta, and that the expression of BMPR1α, an important receptor in the hepcidin signaling pathway, was upregulated (37). Thus, this mouse model is suitable for investigation of iron metabolism in insulin metabolic abnormalities, where osteogenesis imperfecta is manifested as one of the main pathological changes.…”

Endoplasmic reticulum stress remodels alveolar bone formation after tooth extraction

“…Type I collagen has been reported to enhance osteoblastic differentiation and bone formation. 42 Our previous study 43 We demonstrated that osteoblasts could restore their proliferation and osteogenic ability when salubrinal is used to inhibit ER stress and verified that ER stress occurs after tooth extraction.…”

<p>Serum miR-503 is a Candidate Biomarker for Differentiating Metabolic Healthy Obesity from Metabolic Unhealthy Obesity</p>

“…13 In our previous study, we identified miR-503 as the differential expressed gene in insulin receptor substrate-1 (IRS-1) KO mice with a decrease in fat mass. 14 And bone morphogenetic proteins receptor type 1A (BMPR1a), the target gene of miR-503, whose express was synchronously declined in IRS-1 KO mice. 15 We further confirmed this finding by transfecting primary preadipocytes with BMPR1A-specific small interfering RNAs (siRNAs), and the results showed a significant disruption of adipogenesis.…”