Interactions between FGF21 and BMP-2 in osteogenesis

Biochem Biophys Res Commun. 2013 Mar 22;432(4):677-82. doi: 10.1016/j.bbrc.2013.02.019. Epub 2013 Feb 14.


Lifestyle-related diseases are increasing and the challenge to create innovative drugs to treat such diseases is a main focus in medical science research. Fibroblast growth factor 21 (FGF21) is a powerful modulator of glucose and lipid metabolism, and is an innovative candidate drug already in clinical trials for type 2 diabetes mellitus and obesity. Bone fragility and impaired fracture healing induced by such lifestyle-related conditions are also a growing problem. Bone morphogenic proteins (BMPs) are well known osteogenic growth factors, and BMP-2 is used to augment bone formation in difficult clinical situations. There are many documented interactions between the FGF and BMP family proteins, although the interaction between FGF21 and BMP-2 remains unknown. The aim of this study was to reveal the effect of FGF21 toward BMP-2-dependent osteogenic activity, using C2C12 cells as a model system. We found that FGF21 enhanced BMP-2-dependent transcription and osteogenesis in the C2C12 cell line, which was confirmed by alkaline phosphatase activity, matrix mineralization, and gene expression. Mechanistically, FGF21 enhanced BMP-2-induced intracellular signaling through Smad proteins, but not through p44/42MAPK proteins. Furthermore, we identified a negative feedback loop in which BMP-2 decreased endogenous FGF21 mRNA expression. In summary, this study demonstrates interactions between BMP-2 and FGF21 pathways exist in vitro, and that FGF21 enhances the osteogenic activity of BMP-2 by up-regulating the BMP-2-dependent Smad signaling pathway.

MeSH terms

  • Bone Morphogenetic Protein 2 / metabolism*
  • Cell Line
  • Chondrocytes / metabolism
  • Fibroblast Growth Factors / genetics
  • Fibroblast Growth Factors / metabolism*
  • Gene Expression Regulation
  • Humans
  • Mitogen-Activated Protein Kinase 1 / metabolism
  • Mitogen-Activated Protein Kinase 3 / metabolism
  • Osteogenesis / genetics
  • Osteogenesis / physiology*
  • Phosphorylation
  • Smad1 Protein / metabolism
  • Smad5 Protein / metabolism
  • Smad8 Protein / metabolism
  • Transcription, Genetic


  • BMP2 protein, human
  • Bone Morphogenetic Protein 2
  • Smad1 Protein
  • Smad5 Protein
  • Smad8 Protein
  • fibroblast growth factor 21
  • Fibroblast Growth Factors
  • Mitogen-Activated Protein Kinase 1
  • Mitogen-Activated Protein Kinase 3