Thyroid hormones regulate fibroblast growth factor receptor signaling during chondrogenesis

Childhood hypothyroidism causes growth arrest with delayed ossification and growth-plate dysgenesis, whereas thyrotoxicosis accelerates ossification and growth. Thyroid hormone (T-3) 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 T-3 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 T-3 during the first 6-12d of culture, when T-3 inhibited proliferation by 50%. FGFR3 expression was also increased in cells treated with T-3 for 21 d, when T-3 induced an earlier onset of hypertrophic differentiation and collagen X expression. FGFR3 expression was reduced in growth plates from T-3 receptor alpha-null mice, which exhibit skeletal hypothyroidism, but was increased in T-3 receptor beta(PV/ PV) mice, which display skeletal thyrotoxicosis. These findings indicate that FGFR3 is a T-3-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 T-3. Thus, T-3 exerted differing effects on FGFR activation during chondrogenesis depending on which FGFligand stimulated the FGFR and which downstream signaling pathway was activated. These studies identify novel interactions between T-3 and FGFs that regulate chondrocyte proliferation and differentiation during chondrogenesis.