Endocrine Abstracts (2004) 7 OC17

Thyroid hormone (T3) activates fibroblast growth factor (FGF) receptor signalling in bone

JC Barnard, AJ Williams, CB Harvey & GR Williams

Molecular Endocrinology Group, Division of Medicine & MRC Clinical Sciences Centre, Imperial College London, UK.

FGFs and T3 are required for skeletal development. Activating mutations of FGF receptor-1 (FGFR-1) and FGFR-2 cause craniosynostosis, whilst FGFR-3 is a negative regulator of chondrocyte proliferation and activating mutations cause achondroplasia. Childhood hypothyroidism causes delayed ossification and growth retardation, whereas thyrotoxicosis accelerates bone development, induces premature growth plate and skull suture closure and causes short stature and craniosynostosis. We hypothesised that FGFR-activated pathways lie downstream of T3 and recently showed that T3 stimulates FGFR-1 expression and enhances FGFR-1 signalling in osteoblasts but does not influence FGFR-2 or FGFR-3 expression. Alternative mRNA splicing confers complexity to this system by generating FGFR isoforms with differing ligand binding and signal transduction properties. We investigated T3 effects on FGFR expression and signalling in chondrocytes and osteoblasts. Chondrogenic ATDC5 cells expressed two FGFR-1, three FGFR-2 and one FGFR-3 extra-cellular domain isoforms. Terminally differentiated ROS17/2.8 and pre-osteoblastic UMR106 cells expressed three principal FGFR-1 and FGFR-2 variants and one FGFR-3 isoform. Alternative FGFR mRNA splicing was not regulated by T3 in ATDC5 or osteoblastic cells. ATDC5 cells proliferate over 7-10 days in culture and undergo hypertrophic chondrocyte differentiation after 21 days. Treatment with T3 (100nM) resulted in a 2-3 fold increase in FGFR-1 and FGFR-2 mRNA expression during the proliferative phase, with no T3-stimulation evident in differentiated cells. T3 also stimulated FGFR-3 expression 10-, 8- and 2.5-fold after 6, 12 and 21 days but no induction was evident by 28 days. These findings correlated with a 2.0-2.5 fold T3-enhancement of FGF-stimulated MAPK activation in proliferating ATDC5 cells, which was no longer evident in hypertrophic chondrocytes at day 21. These data demonstrate that regulation of FGFR expression in chondrocytes and osteoblasts by T3 is cell-specific. T3 actions in chondrocytes are primarily mediated via FGFR-3, whereas effects in osteoblasts involve FGFR-1.

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