INTRODUCTION: Fibroblast growth factor (FGF)23 is produced primarily in bone and acts on kidney as a systemic phosphaturic factor; high levels result in rickets and osteomalacia. However, it remains unclear whether FGF23 acts locally and directly on bone formation. MATERIALS AND METHODS: We overexpressed human FGF23 in a stage-specific manner during osteoblast development in fetal rat calvaria (RC) cell cultures by using the adenoviral overexpression system and analyzed its effects on osteoprogenitor proliferation, osteoid nodule formation, and mineralization. Bone formation was also measured by calcein labeling in parietal bone organ cultures. Finally, we addressed the role of tyrosine phosphorylation of FGF receptor (FGFR) in mineralized nodule formation. RESULTS: Nodule formation and mineralization, but not osteoprogenitor proliferation, were independently suppressed by overexpression of FGF23 in RC cells. Increased FGF23 levels also suppressed bone formation in the parietal bone organ culture model. FGF23 overexpression enhanced phosphorylation of FGFR, whereas the impairment of mineralized nodule formation by FGF23 overexpression was abrogated by SU5402, an inhibitor of FGFR1 tyrosine kinase activity. CONCLUSIONS: These studies suggest that FGF23 overexpression suppresses not only osteoblast differentiation but also matrix mineralization independently of its systemic effects on Pi homeostasis.
INTRODUCTION: Fibroblast growth factor (FGF)23 is produced primarily in bone and acts on kidney as a systemic phosphaturic factor; high levels result in rickets and osteomalacia. However, it remains unclear whether FGF23 acts locally and directly on bone formation. MATERIALS AND METHODS: We overexpressed humanFGF23 in a stage-specific manner during osteoblast development in fetal rat calvaria (RC) cell cultures by using the adenoviral overexpression system and analyzed its effects on osteoprogenitor proliferation, osteoid nodule formation, and mineralization. Bone formation was also measured by calcein labeling in parietal bone organ cultures. Finally, we addressed the role of tyrosine phosphorylation of FGF receptor (FGFR) in mineralized nodule formation. RESULTS: Nodule formation and mineralization, but not osteoprogenitor proliferation, were independently suppressed by overexpression of FGF23 in RC cells. Increased FGF23 levels also suppressed bone formation in the parietal bone organ culture model. FGF23 overexpression enhanced phosphorylation of FGFR, whereas the impairment of mineralized nodule formation by FGF23 overexpression was abrogated by SU5402, an inhibitor of FGFR1tyrosine kinase activity. CONCLUSIONS: These studies suggest that FGF23 overexpression suppresses not only osteoblast differentiation but also matrix mineralization independently of its systemic effects on Pi homeostasis.
Authors: Christian Faul; Ansel P Amaral; Behzad Oskouei; Ming-Chang Hu; Alexis Sloan; Tamara Isakova; Orlando M Gutiérrez; Robier Aguillon-Prada; Joy Lincoln; Joshua M Hare; Peter Mundel; Azorides Morales; Julia Scialla; Michael Fischer; Elsayed Z Soliman; Jing Chen; Alan S Go; Sylvia E Rosas; Lisa Nessel; Raymond R Townsend; Harold I Feldman; Martin St John Sutton; Akinlolu Ojo; Crystal Gadegbeku; Giovana Seno Di Marco; Stefan Reuter; Dominik Kentrup; Klaus Tiemann; Marcus Brand; Joseph A Hill; Orson W Moe; Makoto Kuro-O; John W Kusek; Martin G Keane; Myles Wolf Journal: J Clin Invest Date: 2011-10-10 Impact factor: 14.808
Authors: Nisha Bansal; Ronit Katz; Ian H de Boer; Bryan Kestenbaum; David S Siscovick; Andrew N Hoofnagle; Russell Tracy; Gail A Laughlin; Michael H Criqui; Mathew J Budoff; Dong Li; Joachim H Ix Journal: J Clin Endocrinol Metab Date: 2013-10-03 Impact factor: 5.958