Characterization of specific thyroid hormone receptors in bone

Abstract

Thyroid hormones stimulate bone turnover in vivo and increase Ca release from bone in vitro. To investigate further the effects of thyroid hormones in bone, we have characterized specific nuclear receptors for [125I]tri-iodothyronine (T3) in neonatal mouse calvaria. Maximal specific binding of [125I]T3 to isolated nuclei occurred within 60 min at 22 degrees C. [125I]T3 binding was completely and rapidly displaced by the addition of 10(-6) M unlabeled T3; the dissociation appears to be first order with t1/2 = 36 min. The IC50 for competition by unlabeled T3 was approximately 10(-8) M. The relative affinity of thyroxine (T4) for the receptor was approximately 10 X lower than T3, consistent with its lower biological potency in most target tissues for thyroid hormones. Only weak competition was observed with diiodotyrosine at concentrations up to 10(-4) M. We have previously shown that the cardiotonic agent milrinone stimulates bone resorption in vitro with characteristics similar to those of T4. Structural homology between milrinone and T4 was recently reported. Milrinone, like diiodotyrosine, was only a weak competitor for binding at concentrations up to 10(-4) M. Milrinone inhibited collagen synthesis in the calvaria. The results suggest that the effects of milrinone on bone turnover in calvaria in vitro are probably not mediated through a thyroid hormone receptor.

Bone-resorbing activity of thyroid hormones is related to prostaglandin production in cultured neonatal mouse calvaria

“…A biologic potency of T, 10 times higher than that of T, has been observed in many tissues, including bone, and is thought to be related to a similar difference in the binding affinity of the thyroid hormone receptor for T, and T4. (36)(37)(38) Thus, it can be inferred from our data that stimulation of bone resorption by thyroid hormones in cultured neonatal mouse calvaria also involves a receptor-mediated event.…”

Role of Thyroid Hormones in Skeletal Development and Bone Maintenance

“…Studies of mixed cultures containing osteoclast lineage cells and bone marrow stromal cells have been contradictory and it is not clear whether stimulation of osteoclastic bone resorption results from direct T3-actions in osteoclasts or indirect effects mediated by primary actions in cells of the osteoblast lineage (186 -188, 254, 266). Studies of fetal long bone and calvarial cultures (173,267,268) implicated various cytokines and growth factors including IGF-1 (269,270), prostaglandins (186), interleukins (271), TGF␤ (238, 272), and interferon-␥ (186) as mediators of secondary responses in osteoclasts. Similarly, treatment of immortalized osteoblasts or primary bone marrow stromal cells resulted in increased RANKL, interleukin 6 (IL-6), IL-8 and prostaglandin E2 expression, and inhibition of OPG, consistent with an indirect effect of thyroid hormones on osteoclast function (254,258,266).…”

Disruption of BMP Signaling Prevents Hyperthyroidism-Induced Bone Loss in Male Mice

“…Several studies consent that T 3 promotes osteogenic differentiation and enhances the synthesis of bone matrix in murine osteoblasts. (10)(11)(12)(13)(14)(15)(16) Besides, nuclear TH receptors (TR), TRα1 and TRβ1, (17)(18)(19)(20) are expressed in osteoblasts, providing evidence that TH may exert direct effects on osteoblasts. We previously reported that exogenously applied TH enhances bone turnover with an upregulation of both bone formation and predominantly bone resorption, leading to high turnover bone loss in male mice.…”