miR-218 directs a Wnt signaling circuit to promote differentiation of osteoblasts and osteomimicry of metastatic cancer cells

J Biol Chem. 2012 Dec 7;287(50):42084-92. doi: 10.1074/jbc.M112.377515. Epub 2012 Oct 11.


MicroRNAs (miRNAs) negatively and post-transcriptionally regulate expression of multiple target genes to support anabolic pathways for bone formation. Here, we show that miR-218 is induced during osteoblast differentiation and has potent osteogenic properties. miR-218 promotes commitment and differentiation of bone marrow stromal cells by activating a positive Wnt signaling loop. In a feed forward mechanism, miR-218 stimulates the Wnt pathway by down-regulating three Wnt signaling inhibitors during the process of osteogenesis: Sclerostin (SOST), Dickkopf2 (DKK2), and secreted frizzled-related protein2 (SFRP2). In turn, miR-218 expression is up-regulated in response to stimulated Wnt signaling and functionally drives Wnt-related transcription and osteoblast differentiation, thereby creating a positive feedback loop. Furthermore, in metastatic breast cancer cells but not in normal mammary epithelial cells, miR-218 enhances Wnt activity and abnormal expression of osteoblastic genes (osteomimicry) that contribute to homing and growth of cells metastatic to bone. Thus, miR-218/Wnt signaling circuit amplifies both the osteoblast phenotype and osteomimicry-related tumor activity.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Adaptor Proteins, Signal Transducing
  • Animals
  • Cell Differentiation*
  • Cell Line, Tumor
  • Gene Expression Regulation, Neoplastic*
  • Glycoproteins / genetics
  • Glycoproteins / metabolism
  • Intercellular Signaling Peptides and Proteins / genetics
  • Intercellular Signaling Peptides and Proteins / metabolism
  • Mammary Neoplasms, Animal / genetics
  • Mammary Neoplasms, Animal / metabolism*
  • Mammary Neoplasms, Animal / pathology
  • Membrane Proteins / genetics
  • Membrane Proteins / metabolism
  • Mice
  • MicroRNAs / biosynthesis*
  • MicroRNAs / genetics
  • Neoplasm Metastasis
  • Osteoblasts / metabolism*
  • Osteoblasts / pathology
  • RNA, Neoplasm / biosynthesis*
  • RNA, Neoplasm / genetics
  • Wnt Signaling Pathway*


  • Adaptor Proteins, Signal Transducing
  • Dkk2 protein, mouse
  • Glycoproteins
  • Intercellular Signaling Peptides and Proteins
  • MIRN218 microRNA, mouse
  • Membrane Proteins
  • MicroRNAs
  • RNA, Neoplasm
  • Sfrp2 protein, mouse
  • Sost protein, mouse