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 6-12 d 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, T(3) 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 FGF ligand 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.
Barnard
Joanna C
JC
Molecular Endocrinology Group, Division of Medicine and Medical Research Council Clinical Sciences Centre, Imperial College London, UK.
Williams
Allan J
AJ
Rabier
Bénédicte
B
Chassande
Olivier
O
Samarut
Jacques
J
Cheng
Sheue-Yann
SY
Bassett
J H Duncan
JH
Williams
Graham R
GR
D000818:Animals; D001483:Base Sequence; D002454:Cell Differentiation / Q000502:physiology; D002478:Cells, Cultured; D020219:Chondrogenesis / Q000187:drug effects / Q000502:physiology*; D004789:Enzyme Activation / Q000502:physiology; D051379:Mice; D018345:Mice, Knockout; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D008969:Molecular Sequence Data; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D017468:Receptors, Fibroblast Growth Factor / Q000235:genetics / Q000378:metabolism* / Q000502:physiology; D011988:Receptors, Thyroid Hormone / Q000172:deficiency; D015398:Signal Transduction / Q000502:physiology*; D014284:Triiodothyronine / Q000494:pharmacology / Q000502:physiology*
D020033:Protein Isoforms; D012333:RNA, Messenger; D017468:Receptors, Fibroblast Growth Factor; D011988:Receptors, Thyroid Hormone; D014284:Triiodothyronine; D020928:Mitogen-Activated Protein Kinases