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T3 is essential for normal skeletal development, acting mainly via the TRα1 nuclear receptor. Nevertheless, the mechanisms of T3 action in bone are poorly defined. Fibroblast growth factor receptor-1 (FGFR1) is also essential for bone formation. Fgfr1 expression and activity are positively regulated by T3 in osteoblasts, and in mice that harbor a dominant negative PV mutation targeted to TRα1 or TRβ, Fgfr1 expression is sensitive to skeletal thyroid status. To investigate mechanisms underlying T3 regulation of FGFR1, we obtained primary calvarial osteoblasts from wild-type and TRβPV/PV littermate mice. T3 treatment increased Fgfr1 expression 2-fold in wild-type cells, but 8-fold in TRβPV/PV osteoblasts. The 4-fold increased T3 sensitivity of TRβPV/PV osteoblasts was associated with a markedly increased ratio of TRα1:TRβ1 expression that resulted from reduced TRβ1 expression in TRβPV/PV osteoblasts compared with wild-type. Bioinformatics and gel shift studies, and mutational analysis, identified a specific TR binding site 279–264 nucleotides upstream of the murine Fgfr1 promoter transcription start site. Transient transfection analysis of a series of Fgfr1 promoter 5′-deletion constructs, of a mutant reporter construct, and a series of heterologous promoter constructs, confirmed that this region of the promoter mediates a TR-dependent transcriptional response to T3. Thus, in addition to indirect regulation of FGFR1 expression by T3 reported previously, T3 also activates the Fgfr1 promoter directly via a thyroid hormone response element located at positions −279/−264.

endocrinology

Regulation of Fibroblast Growth Factor Receptor-1 (Fgfr1) by Thyroid Hormone: Identification of a Thyroid Hormone Response Element in the Murine Fgfr1 Promoter