Both retinoic acid and 1,25(OH) 2 vitamin D 3 inhibit thyroid hormone-induced terminal differentiaton of growth plate chondrocytes

Abstract

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) 2 vitamin D 3, 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 and/or 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- trans retinoic acid and 1,25(OH) 2 vitamin D 3 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 1,25(OH) 2 vitamin D 3 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.