Effects of cyclosporins and transforming growth factor β₁ on thyroid hormone action in cultured fetal rat limb bones

To study the mechanism of action of thyroid hormones on bone, we examined the effects of immunosuppresive and nonimmunosuppressive cyclosporins, as well as of transforming growth factor β₁ (TGFβ₁), 17β-estradiol (E₂), and dihydroxytestosterone (DHT) on thyroxine (T₄)-and triiodothyronine (T₃)-stimulated bone resorption in fetal rat limb bones. The immunosuppressive cyclosporins A (CsA) and G (CsG) inhibited thyroid hormone (T₄+T₃)-stimulated resorption and β-glucuronidase release into the culture medium, whereas the weak or nonimmunosuppressive cyclosporins D (CsD) and H (CsH) did not show this effect. Increasing the medium calcium concentration reduced the ability of T₄ to stimulate ⁴⁵Ca release, while not significantly affecting the response to CsA. TGFβ₁ elicited a biphasic effect when administered together with T₄. During the first 3 days of culture, TGFβ₁ elicited a small, nonsignificant decrease in released ⁴⁵Ca; during a subsequent 3 days of culture, it enhanced T₄-stimulated bone resorption significantly. These effects differed from those of TGFβ₁ on parathormone-stimulated resorption. E₂ and DHT did not influence the action of T₄ on bone tissue. These results suggest that the mechanism of action of thyroid hormones on bone may involve immune factors, as well.