Effect of thyroid hormone and its antagonist NH3 on osteoblastic differentiation of human periosteal mesenchimal cells with S252W mutation in FGFR2

• Grant number: 09/53262-7
• Support Opportunities: Regular Research Grants
• Start date: March 01, 2010
• End date: August 31, 2012
• Field of knowledge: Biological Sciences - Morphology
• Principal Investigator: Cecilia Helena de Azevedo Gouveia
• Grantee: Cecilia Helena de Azevedo Gouveia
• Host Institution: Instituto de Ciências Biomédicas (ICB). Universidade de São Paulo (USP). São Paulo , SP, Brazil

Abstract

Recent evidences suggest that thyroid hormone (TH) interacts with fibroblast growth factors (FGF) to regulate bone development, however, little is known about the molecular mechanisms that determine this interplay. The aim of this project is to investigate the interaction of TH with FGF in the osteoblastic differentiation, using human periosteal mesenchimal cells with S252W mutation in the isoform 2 of FGF receptor (FGFR2) as model. This is a gain-of-function mutation, characterized by increased affinity of FGFR2 by the majority of FGFs, and by an abnormal signaling that follows the FGF/FGFR2 interaction. Consequences of this mutation include increased ossification, leading to severe craniosynostosis (premature closure of the cranial sutures) and other skeletal abnormalities. Thus, periosteal mesenchimal cells with S252W mutation are a very interesting model to evaluate a possible interaction between TH and the FGF/FGFR pathway. Using these cells, we will evaluate the effect of TH and its antagonist NH3 in the growth, proliferation, death and differentiation of osteoblasts. In addition, we will evaluate the effect of T3 and NH3 in a FGF/FGFR signaling pathway that was shown to be altered in these cells, the mitogen-activated protein kinase (MAPK) pathway. The investigation of the interaction of TH with FGFs in cells with S252VV mutation may contribute to the development of therapeutic strategies for the treatment of skeletal diseases, including craniosynostosis. (AU)