miR-21 synergizes with BMP9 in osteogenic differentiation by activating the BMP9/Smad signaling pathway in murine multilineage cells

Int J Mol Med. 2015 Dec;36(6):1497-506. doi: 10.3892/ijmm.2015.2363. Epub 2015 Oct 9.


Bone morphogenetic proteins (BMPs), particularly BMP9, have been shown to promote the osteogenic differentiation of murine multilineage cells (MMCs) and to promote bone formation in bone diseases; however, the mechanisms involved remain poorly understood. MicroRNAs (miRNAs or miRs) have been proven to regulate mesenchymal stem cell (MSC) differentiation. In this study, we identified a novel mechanism that unravels the functional axis of a key miRNA (miR-21) which contributes to BMP9‑induced osteogenic differentiation. We screened differentially expressed miRNAs in MMCs during BMP9‑induced osteogenic differentiation and found that miR-21 was significantly upregulated by BMP9 during the osteogenesis of MMCs. Furthermore, miR-21 was confirmed to promote the osteogenic differentiation of the MMCs by suppressing Smad7, which negatively regulates the osteogenic differentiation of MMCs. The upregulation of miR-21 may promote the osteogenic differentiation of MMCs in synergy with BMP9. The findings of our study revealed a novel function of miR-21, and suggest that the overexpression of miR-21 contributes to bone formation by promoting BMP9‑induced osteogenic differentiation. Our data may provide a molecular basis for the development of novel therapeutic strategies to treat bone diseases, such as osteoporosis and other inflammatory bone diseases.

MeSH terms

  • 3' Untranslated Regions / genetics
  • Alkaline Phosphatase / metabolism
  • Blotting, Western
  • Calcium / metabolism
  • Cell Differentiation / genetics*
  • Cell Line
  • Cells, Cultured
  • Embryo, Mammalian / cytology
  • Embryo, Mammalian / metabolism
  • Fibroblasts / cytology
  • Fibroblasts / metabolism
  • Gene Expression
  • Growth Differentiation Factor 2 / genetics*
  • Growth Differentiation Factor 2 / metabolism
  • HCT116 Cells
  • HEK293 Cells
  • Humans
  • MicroRNAs / genetics*
  • Myoblasts / cytology
  • Myoblasts / metabolism
  • Osteocalcin / genetics
  • Osteocalcin / metabolism
  • Osteogenesis / genetics*
  • Reverse Transcriptase Polymerase Chain Reaction
  • Signal Transduction / genetics*
  • Smad7 Protein / genetics*
  • Smad7 Protein / metabolism


  • 3' Untranslated Regions
  • Gdf2 protein, mouse
  • Growth Differentiation Factor 2
  • MIRN21 microRNA, mouse
  • MicroRNAs
  • Smad7 Protein
  • Smad7 protein, mouse
  • Osteocalcin
  • Alkaline Phosphatase
  • Calcium