Thyroid Hormone Activates Fibroblast Growth Factor Receptor-1 in Bone

• Published in: Molecular endocrinology (Baltimore, Md.) Md.), 2003-09, Vol.17 (9), p.1751-1766
• Main Authors: Stevens, David A, Harvey, Clare B, Scott, Anthea J, O’Shea, Patrick J, Barnard, Joanna C, Williams, Allan J, Brady, Gerard, Samarut, Jacques, Chassande, Olivier, Williams, Graham R
• Format: Article
• Language: English
• Subjects: Animals; Bone and Bones - metabolism; Computer Science; Fibroblast Growth Factor 2 - metabolism; Life Sciences; Mice; Mitogen-Activated Protein Kinases - metabolism; Osteoblasts - metabolism; Phosphorylation - drug effects; Phosphotransferases - drug effects; Pyrimidines - pharmacology; Receptor Protein-Tyrosine Kinases - drug effects; Receptor Protein-Tyrosine Kinases - genetics; Receptor Protein-Tyrosine Kinases - metabolism; Receptor, Fibroblast Growth Factor, Type 1; Receptors, Fibroblast Growth Factor - drug effects; Receptors, Fibroblast Growth Factor - genetics; Receptors, Fibroblast Growth Factor - metabolism; Signal Transduction - physiology; Thyroid Gland - metabolism; Triiodothyronine - metabolism; Urea - analogs & derivatives; Urea - pharmacology
• ISSN: 0888-8809; 1944-9917
• DOI: 10.1210/me.2003-0137

Thyroid hormone (T3) and the T3 receptor (TR) α 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 TRα-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 TRα-null osteoblasts. These findings implicate FGFR1 signaling in T3-dependent bone development and the pathogenesis of skeletal disorders resulting from thyroid disease.