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Thyroid Hormone Activates Fibroblast Growth Factor Receptor-1 in Bone

Molecular Endocrinology Group (D.A.S., C.B.H., A.J.S., P.J.O’S., J.C.B., A.J.W., G.R.W.), Division of Medicine and Medical Research Council Clinical Sciences Centre, Faculty of Medicine, Imperial College London, London W12 0NN, United Kingdom; Epistem Ltd. and School of Biological Sciences (G.B.), University of Manchester, Manchester M13 9PT, United Kingdom; Laboratoire de Biologie Moléculaire et Cellulaire de l’ENS de Lyon (J.S., O.C.), Unité Mixte de Recherche 5665 Centre National Recherche Scientifique, LA 913 Institut National de la Recherche Agronomique, 69364 Lyon Cedex 07, France; and Unité Institut National de la Santé et de la Recherche Médicale Unité-443 (O.C.), Université Victor Segalen Bordeaux 2, 33076 Bordeaux Cedex 02, France

Address all correspondence and requests for reprints to: Dr. G. R. Williams, Molecular Endocrinology Group, Medical Research Council Clinical Sciences Centre, Clinical Research Building, 5th Floor, Hammersmith Hospital, Du Cane Road, London W12 0NN, United Kingdom. E-mail: graham.williams{at}imperial.ac.uk.

Thyroid hormone (T₃) and the T₃ receptor (TR) gene are essential for bone development whereas adult hyperthyroidism increases the risk of osteoporotic fracture. We isolated fibroblast growth factor receptor-1 (FGFR1) as a T₃-target gene in osteoblasts by subtraction hybridization. FGFR1 mRNA was induced 2- to 3-fold in osteoblasts treated with T₃ for 6–48 h, and FGFR1 protein was stimulated 2- to 4-fold. Induction of FGFR1 was independent of mRNA half-life and abolished by actinomycin D and cycloheximide, indicating the involvement of an intermediary protein. Fibroblast growth factor 2 (FGF2) stimulated MAPK in osteoblasts, and pretreatment with T₃ for 6 h induced a more rapid response to FGF that was increased in magnitude by 2- to 3-fold. Similarly, T₃ enhanced FGF2-activated autophosphorylation of FGFR1, but did not modify FGF2-induced phosphorylation of the docking protein FRS2. These effects were abolished by the FGFR-selective inhibitors PD166866 and PD161570. In situ hybridization analyses of TR-knockout mice, which have impaired ossification and skeletal mineralization, revealed reduced FGFR1 mRNA expression in osteoblasts and osteocytes, whereas T₃ failed to stimulate FGFR1 mRNA or enhance FGF2-activated MAPK signaling in TR-null osteoblasts. These findings implicate FGFR1 signaling in T₃-dependent bone development and the pathogenesis of skeletal disorders resulting from thyroid disease.

NURSA Molecule Pages Link:

Nuclear Receptors:   TRα

Ligands:   Thyroid hormone

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