A single-point mutation in FGFR2 affects cell cycle and Tgfß signalling in osteoblasts

Kingyin M.A. Lee , Leonor Santos-Ruiz , Patrizia Ferretti

Fgf and Tgfß are key regulators of bone development. It is not known, however, whether there is a relationship between defective Fgf signalling, resulting in a premature cranial suture fusion, and Tgfß signalling. We used mouse calvaria osteoblasts carrying a mutation (hFGFR2-C278F) associated with Crouzon and Pfeiffer syndromes to investigate effects of this mutation on cell growth and possible mechanisms underlying it. Mutated osteoblasts displayed reduced S-phase, increased apoptosis and increased differentiation. As Tgfß signalling appeared to be required in an autocrine/paracrine manner for osteoblast proliferation, we tested the hypothesis that reduced growth might be due, at least in part, to an altered balance between FGF and Tgfß signalling. Tgfß expression was indeed decreased in mutated osteoblasts, as compared to osteoblasts carrying the wild type hFGFR2. Treatment with Tgfß, however, neither increased proliferation in mutated osteoblasts, unlike in controls, nor rescued proliferation in control osteoblasts treated with an Erk1/2 inhibitor. Significantly, Erk2, that is important for proliferation, was reduced relatively to Erk1 in mutated cells. Altogether this study suggests that the hFGFR2-C278F mutation affects the osteoblast ability to respond to Tgfß stimulation via the Erk pathway and that the overall effect of the mutation is a loss of function.

Mots clés: craniosynostosis; fibroblast growth factor receptor 2; mutation; osteoblast; proliferation; transforming growth factor beta

Kingyin M.A. Lee, Leonor Santos-Ruiz, Patrizia Ferretti. A single-point mutation in FGFR2 affects cell cycle and Tgfß signalling in osteoblasts. Biochimica et Biophysica Acta - Molecular Basis of Disease, 2010, 1802 (3), pp.347. ⟨10.1016/j.bbadis.2009.11.006⟩. ⟨hal-00560299⟩