Both retinoic acid and 1,25(OH)₂ vitamin D₃ 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)? 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

Differential regulation of MMPs and matrix assembly in chicken and turkey growth-plate chondrocytes

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Primary cilia modulate Ihh signal transduction in response to hydrostatic loading of growth plate chondrocytes

“…We have previously shown that this pellet culture system allows cells to terminally differentiate into hypertrophic chondrocytes that express high levels of alkaline phosphatase and type X collagen [39]. We used our custom-designed loading system to apply an intermittent hydrostatic compression force on these cell pellets, which resulted a markedly increased Ihh expression.…”

Thyroid Hormone and the Skeleton

“…Thyroid hormone exerts direct effects on chondrocytes [11][12][13][14] and is necessary for normal chondrocyte development [15] and endochondral ossification of the growth plate [16]. Children with hypothyroidism have reduced thickness of the growth plate of long bones, disorganization of the normal cartilage columns of the growth plate, and impaired differentiation of growth plate chondrocytes into hypertrophic cells resulting in growth retardation [15].…”