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Thyroid Hormones Regulate Fibroblast Growth Factor Receptor Signaling during Chondrogenesis

Molecular Endocrinology Group (J.C.B., A.J.W., J.H.D.B., G.R.W.), Division of Medicine and Medical Research Council Clinical Sciences Centre, Imperial College London, Hammersmith Campus, London W12 0NN, United Kingdom; Institut National de la Santé et de la Recherche Médicale Unité 443 (B.R., O.C.), Université Victor Segalen Bordeaux 2, Bordeaux, France; Laboratoire de Biologie Moléculaire et Cellulaire de l’Ecole Normale Supérieur de Lyon (J.S.), Unité Mixte de Recherche 5665 Centre National de la Recherche Scientifique, LA 913 Institut National de la Recherche Agronomique, Lyon, France; and Gene Regulation Section (S.-y.C.), Laboratory of Molecular Biology, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892-4264

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

Childhood hypothyroidism causes growth arrest with delayed ossification and growth-plate dysgenesis, whereas thyrotoxicosis accelerates ossification and growth. Thyroid hormone (T₃) regulates chondrocyte proliferation and is essential for hypertrophic differentiation. Fibroblast growth factors (FGFs) are also important regulators of chondrocyte proliferation and differentiation, and activating mutations of FGF receptor-3 (FGFR3) cause achondroplasia. We investigated the hypothesis that T₃ regulates chondrogenesis via FGFR3 in ATDC5 cells, which undergo a defined program of chondrogenesis. ATDC5 cells expressed two FGFR1, four FGFR2, and one FGFR3 mRNA splice variants throughout chondrogenesis, and expression of each isoform was stimulated by T₃ during the first 6–12 d of culture, when T₃ inhibited proliferation by 50%. FGFR3 expression was also increased in cells treated with T₃ for 21 d, when T₃ induced an earlier onset of hypertrophic differentiation and collagen X expression. FGFR3 expression was reduced in growth plates from T₃ receptor -null mice, which exhibit skeletal hypothyroidism, but was increased in T₃ receptor ß^PV/PV mice, which display skeletal thyrotoxicosis. These findings indicate that FGFR3 is a T₃-target gene in chondrocytes. In further experiments, T₃ enhanced FGF2 and FGF18 activation of the MAPK-signaling pathway but inhibited their activation of signal transducer and activator of transcription-1. FGF9 did not activate MAPK or signal transducer and activator of transcription-1 pathways in the absence or presence of T₃. Thus, T₃ exerted differing effects on FGFR activation during chondrogenesis depending on which FGF ligand stimulated the FGFR and which downstream signaling pathway was activated. These studies identify novel interactions between T₃ and FGFs that regulate chondrocyte proliferation and differentiation during chondrogenesis.

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