Endocrine Abstracts

Thyrotoxicosis results in osteoporosis and thyroid hormone (T₃) stimulates osteoclastic bone resorption by unknown mechanisms. We previously demonstrated that knockout mice lacking thyroid hormone receptor α (TRα^0/0) are euthyroid but have high bone mass, whereas mice lacking TRβ (TRβ^−/−) are thyrotoxic and have osteoporosis. Tartrate resistant acid phosphatase (TRAcP) staining revealed osteoclast numbers were reduced by 13% (P<0.05) in TRα^0/0 mice, but increased by 20% (P<0.05) in TRβ^−/− mice, suggesting T₃ acts via TRα to stimulate osteoclastogenesis and bone resorption.

To test this hypothesis, we stimulated bone marrow (BM) from WT, TRα^0/0 and TRβ^−/− mice with M-CSF (25 ng/ml) and RANKL (10 ng/ml) in the absence or presence of T₃ (100 nM). T₃ had no effect on the number, size or survival of osteoclasts of any genotype demonstrating T₃ does not exert direct actions in osteoclasts. Despite this, threefold (P<0.001) greater numbers of osteoclasts formed in cultures from TRα^0/0 mice compared to WT or TRβ^−/−, indicating impaired osteoclast precursor cell differentiation in vivo in TRα^0/0 mice. WT, TRα^0/0 or TRβ^−/− BM was co-cultured with WT osteoblasts in the absence and presence of T₃, but without addition of M-CSF and RANKL. There was a 35–66% (P<0.05) increase in osteoclast number and TRAcP activity following T₃ treatment in all these co-cultures, indicating impaired osteoclastogenesis in TRα^0/0 mice does not result from an osteoclast defect. We next co-cultured WT BM with WT, TRα^0/0 or TRβ^−/− osteoblasts in the absence or presence of T₃. T₃ treatment resulted in a 45–68% increase (P<0.01) in osteoclast number and TRAcP activity when WT BM was co-cultured with WT and TRβ^−/− osteoblasts. By contrast, few osteoclasts formed in co-cultures of WT BM with TRα^0/0 osteoblasts in the absence or presence of T₃.

Overall, these data demonstrate that T₃ stimulates bone resorption indirectly via TRα-dependent actions in osteoblasts.