Bone Abstracts

Childhood hypothyroidism results in delayed skeletal maturation and impaired growth. Thyroid hormones act via temporo-spatially regulated thyroid hormone receptors α (TRα) and (TRβ).

In the skeleton, TRα is the predominant receptor and 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.

WT hypo mice had increased bone mineral content (BMC) by 26 kV point projection digital X-ray microscopy analysis compared to eu controls (P<0.001, n=6). Trabecular bone volume (BV/TV) by μCT (4.3 μm voxel) was elevated in WT hypo 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 WT hypo 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). TRβ^−/− hypo 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, TRα^0/0 hypo 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 TRα^0/0 hypo mice compared to controls (0.18±0.07, 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 TRα^0/0 hypo mice, although reduced compared to controls, was fourfold higher than WT hypo or TRβ^−/− hypo mice.

In conclusion, these studies indicate that TRα has a key role in the skeletal response to hypothyroidism.

Declaration of funding

Funded by a MRC clinical research training grant.