Thyroid Hormones Regulate Fibroblast Growth Factor Receptor Signaling during Chondrogenesis

Childhoodhypothyroidismcausesgrowtharrestwithdelayed 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 T3regulates 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 T3receptor-null mice, which exhibit skeletal hypothyroidism, but was increased in T3 receptor PV/PV mice, which display skeletal thyrotoxicosis. These findings indicate that FGFR3 is a T3target 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 dependingonwhichFGFligandstimulatedtheFGFRandwhich downstream signaling pathway was activated. These studies identifynovelinteractionsbetweenT3andFGFsthatregulate chondrocyte proliferation and differentiation during chondrogenesis. (Endocrinology 146: 5568–5580, 2005)