Endocrine Abstracts

Thyroid hormones stimulate bone formation and linear growth in children. Paradoxically, childhood thyrotoxicosis causes short stature and craniosynostosis due to early closure of the growth plates and skull sutures. In adults, however, thyroid hormone excess increases bone turnover and results in progressive bone loss and osteoporosis. Activating mutations of fibroblast growth factor receptor-3 (FGFR3) cause achondroplastic dwarfism and we have shown that T3 augments FGFR signalling during chondrogenesis. Activating mutations of FGFRs 1-3 also cause discrete craniosynostosis syndromes, and we therefore investigated whether T3 stimulation of osteoblastogenesis correlated with T3 regulation of FGFR expression. Primary mouse osteoblasts undergo an established 28-day programme of differentiation and bone nodule formation in vitro. Cells were cultured in the absence or presence of T3 (100nM) and examined at days 7 (cell proliferation), 14 (osteoblast maturation), 21 (terminal differentiation) and 28 (mineralization). Primary osteoblasts expressed two FGFR1 mRNAs, four FGFR2 mRNAs, two FGFR3 mRNAs and a single FGFR4 isoform at all time points. Maximal T3-induction of FGFR expression occurred at day 14 (FGFR1, 3.43-fold, P<0.01; FGFR3, 5.45-fold, P<0.01; FGFR4, 7.92-fold, P<0.001), and was associated with increased expression of key osteoblast differentiation marker genes (osterix, 11-fold, P<0.01; Runx-2 1.3-fold, P<0.05; osteocalcin, 1.5-fold, P<0.05). Furthermore, T3 stimulated alkaline phosphatase activity from day 14 (day 14, 3.36-fold, P<0.001; day 21, 1.52-fold, P<0.01; day 28, 1.45-fold, P<0.01) but, surprisingly, inhibited bone nodule mineralization at day 28 (P<0.01). These data demonstrate that T3 stimulation of FGFR1, 3 and 4 expression correlates with induction of osteoblast differentiation and suggest that, like chondrogenesis, T3-induced osteoblastogenesis involves augmentation of FGF signalling by T3. By contrast, T3 inhibited the mineralization activity of mature osteoblasts, suggesting a mechanism by which T3-excess stimulates high bone turnover with net loss of mineralised bone in adults.