Although thyroid hormone has been known for many years to be a potent regulator of skeletal maturation in vivo, it has not definitively been determined whether this effect is a result of a direct or indirect action of the hormone. Previous in vivo studies have suggested that thyroid hormone may stimulate longitudinal bone growth by increasing the secretion of growth hormone; however, growth hormone alone is unable to stimulate cartilage maturation. There are also indications that thyroid hormone is able to act directly on growth plate chondrocytes through growth hormone-independent mechanisms. In this study, we demonstrate that rat growth plate chondrocytes in vivo express genes encoding three of the four isoforms of the thyroid hormone receptors described to date, but the corresponding protein can only be detected for the TR␣1 and TR1 isoforms of the receptor. As has been noted in other tissues, there is generally poor correlation between the mRNA levels for each isoform and the relative amount of corresponding protein as measured by immunoblotting, suggesting the possibility that receptor expression may be regulated by post-transcriptional mechanisms. (J Bone Miner Res 1999;14:1550-1556)
Thyroid hormone has been known for over 50 years to be a potent regulator of skeletal maturation at the growth plate. The receptor for thyroid hormone has been discovered to be a member of the nuclear hormone receptor superfamily. Retinoic acid and 1,25(OH)? vitamin D3. whose receptors also belong to this nuclear hormone receptor family, have been implicated in the control of chondrocyte proliferation and differentiation at the growth plate. Recent studies demonstrate that the receptors for thyroid hormone, retinoic acid, and vitamin D bind to a similar DNA response element in the promoter region of target genes and may form heterodimers to regulate gene transcription in target cells. These observations led us to hypothesize that the retinoic acid andlor vitamin D signaling pathways may interact with thyroid hormone signaling at the molecular level to modulate growth plate chondrocyte differentiation. Using a chemically defined, serum-free model of growth plate chondrocyte maturation, both all-mim retinoic acid and 1 ,?5(0H): vitamin D3 markedly inhibited thyroid hormone-induced terminal differentiation in a dose-dependent manner. In the absence of thyroid hormone, retinoic acid stimulated alkaline phosphatase activity modestly at the highest dose used. however neither retinoic acid nor 1,95(0H)2 vitamin D3 induced expression of type X collagen mRNA. We conclude that retinoic acid and vitamin D are likely to be antagonists of thyroid hormone signaling in the growth plate. C) 9001 Orthopaedic Reserach Society. Published by
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