title: miR-542-3p suppresses osteoblast cell proliferation and differentiation, targets BMP-7 signaling and inhibits bone formation.
abstract: MicroRNAs (miRNAs) are short non-coding RNAs that interfere with translation of specific target mRNAs and thereby regulate diverse biological processes. Recent studies have suggested that miRNAs might have a role in osteoblast differentiation and bone formation. Here, we show that miR-542-3p, a well-characterized tumor suppressor whose downregulation is tightly associated with tumor progression via C-src-related oncogenic pathways, inhibits osteoblast proliferation and differentiation. miRNA array profiling in Medicarpin (a pterocarpan with proven bone-forming effects) induced mice calvarial osteoblast cells and further validation by quantitative real-time PCR revealed that miR-542-3p was downregulated during osteoblast differentiation. Over-expression of miR-542-3p inhibited osteoblast differentiation, whereas inhibition of miR-542-3p function by anti-miR-542-3p promoted expression of osteoblast-specific genes, alkaline phosphatase activity and matrix mineralization. Target prediction analysis tools and experimental validation by luciferase 3' UTR reporter assay identified BMP-7 (bone morphogenetic protein 7) as a direct target of miR-542-3p. It was seen that over-expression of miR-542-3p leads to repression of BMP-7 and inhibition of BMP-7/PI3K- survivin signaling. This strongly suggests that miR-542-3p suppresses osteogenic differentiation and promotes osteoblast apoptosis by repressing BMP-7 and its downstream signaling. Furthermore, silencing of miR-542-3p led to increased bone formation, bone strength and improved trabecular microarchitecture in sham and ovariectomized (Ovx) mice. Although miR-542-3p is known to be a tumor repressor, we have identified second complementary function of miR-542-3p where it inhibits BMP-7-mediated osteogenesis. Our findings suggest that pharmacological inhibition of miR-542-3p by anti-miR-542-3p could represent a therapeutic strategy for enhancing bone formation in vivo.
authors: Division of Endocrinology and Centre for Research in Anabolic Skeletal Targets in Health and Illness (ASTHI), Lucknow, India.
authors: J
authors: J
authors: Kureel
authors: Division of Endocrinology and Centre for Research in Anabolic Skeletal Targets in Health and Illness (ASTHI), Lucknow, India.
authors: M
authors: M
authors: Dixit
authors: Division of Endocrinology and Centre for Research in Anabolic Skeletal Targets in Health and Illness (ASTHI), Lucknow, India.
authors: A M
authors: AM
authors: Tyagi
authors: Division of Endocrinology and Centre for Research in Anabolic Skeletal Targets in Health and Illness (ASTHI), Lucknow, India.
authors: M N
authors: MN
authors: Mansoori
authors: Division of Endocrinology and Centre for Research in Anabolic Skeletal Targets in Health and Illness (ASTHI), Lucknow, India.
authors: K
authors: K
authors: Srivastava
authors: Division of Medicinal & Process Chemistry, CSIR-Central Drug Research Institute, B.S. 10/1, Sector-10, Jankipuram Extension, Lucknow, India.
authors: A
authors: A
authors: Raghuvanshi
authors: Division of Medicinal & Process Chemistry, CSIR-Central Drug Research Institute, B.S. 10/1, Sector-10, Jankipuram Extension, Lucknow, India.
authors: R
authors: R
authors: Maurya
authors: Division of Endocrinology and Centre for Research in Anabolic Skeletal Targets in Health and Illness (ASTHI), Lucknow, India.
authors: R
authors: R
authors: Trivedi
authors: Division of Medicinal & Process Chemistry, CSIR-Central Drug Research Institute, B.S. 10/1, Sector-10, Jankipuram Extension, Lucknow, India.
authors: A
authors: A
authors: Goel
authors: Division of Endocrinology and Centre for Research in Anabolic Skeletal Targets in Health and Illness (ASTHI), Lucknow, India.
authors: D
authors: D
authors: Singh
mesh_terms: D000818:Animals; D055419:Bone Morphogenetic Protein 7 / Q000235:genetics* / Q000378:metabolism; D002454:Cell Differentiation; D049109:Cell Proliferation; D002478:Cells, Cultured; D015536:Down-Regulation; D005260:Female; D018507:Gene Expression Regulation, Developmental; D051379:Mice; D008807:Mice, Inbred BALB C; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism*; D010006:Osteoblasts / Q000166:cytology* / Q000378:metabolism; D010012:Osteogenesis; D015398:Signal Transduction
chemical_list: D055419:Bone Morphogenetic Protein 7; C572448:MIRN542 microRNA, mouse; D035683:MicroRNAs