title: Interactions between FGF21 and BMP-2 in osteogenesis.
abstract: 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.
authors: Lawrence J.Ellison Musculoskeletal Research Center, Department of Orthopaedic Surgery, University of California Davis, 4635 Second Avenue, Sacramento, CA 95817, USA.
authors: Kazunari
authors: K
authors: Ishida
authors: Dominik R
authors: DR
authors: Haudenschild
mesh_terms: D055396:Bone Morphogenetic Protein 2 / Q000378:metabolism*; D002460:Cell Line; D019902:Chondrocytes / Q000378:metabolism; D005346:Fibroblast Growth Factors / Q000235:genetics / Q000378:metabolism*; D005786:Gene Expression Regulation; D006801:Humans; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D010012:Osteogenesis / Q000235:genetics / Q000502:physiology*; D010766:Phosphorylation; D051898:Smad1 Protein / Q000378:metabolism; D051902:Smad5 Protein / Q000378:metabolism; D051904:Smad8 Protein / Q000378:metabolism; D014158:Transcription, Genetic
chemical_list: C525718:BMP2 protein, human; D055396:Bone Morphogenetic Protein 2; D051898:Smad1 Protein; D051902:Smad5 Protein; D051904:Smad8 Protein; C414620:fibroblast growth factor 21; D005346:Fibroblast Growth Factors; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3