Endocrine Abstracts

Childhood hypothyroidism results in delayed skeletal maturation and impaired growth. Thyroid hormones act via thyroid hormone receptors α (TRα) and TRβ which are tempo-spatially regulated. In the skeleton, TRα is the predominant receptor, thus we hypothesise that the skeletal effects of hypothyroidism are mediated by TRα. To investigate this we assessed the response of wild type (wt), TRα knockout (TRα^0/0) and TRβ knockout (TRβ^−/−) mice to hypothyroidism. Adult mice from each genotype were rendered/remained hypothyroid (hypo) or euthyroid (eu) for six weeks before skeletal phenotyping. Hypo wt mice had increased bone mineral content (BMC) by faxitron analysis compared to eu controls. (P<0.001, n=6). Trabecular bone volume (BV/TV) by micro CT was elevated in hypo wt mice compared to controls (15.6±1.3 vs 10.9±1.1%, mean±S.E.M., n=5–6, P<0.05 t-test). Bone formation rate (BFR) in hypo wt mice was reduced compared to controls (0.04±0.03 vs 0.45±0.04 μm³/μm² per day, mean±S.E.M., P<0.001 students t-test, n=4). Hypo TRβ^−/− mice also had increased BMC (P<0.001, n=6) and BV/TV (13.4±0.8% vs 7.7±0.8%, P<0.001, n=5–6) and BFR was similarly reduced compared to controls (0.03±0.01 vs 0.33±0.06 μm³/μm² per day, P<0.01, n=4). In contrast to wt and TRβ^−/− mice, hypo TRα^0/0 mice had similar BMC (P=NS, n=6) and BV/TV (12.1±0.5% vs 13.1±0.4%, P=NS, n=5–6) compared to controls. BFR was reduced in hypo TRα^0/0 mice compared to controls (0.18±0.07 vs 0.53±0.04 μm³/μm² per day, P<0.001, n=4). In summary, wt and TRβ^−/− mice had similar responses to hypothyroidism resulting in increased BMC and BV/TV and reduced BFR. In contrast, TRα^0/0 mice showed no change in BMC or BV/TV. BFR in hypo TRα^0/0 mice, although reduced compared to controls, was fourfold higher than hypo wt or TRβ^−/− mice. In conclusion these studies indicate that TRα has a key role in the skeletal response to hypothyroidism.