Thyroid Hormone Interacts With the Wnt/β-Catenin Signaling Pathway in the Terminal Differentiation of Growth Plate Chondrocytes

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Abstract
Thyroid hormone activates Wnt-4 expression and Wnt/beta-catenin signaling in rat growth plate chondrocytes. Wnt antagonists Frzb/sFRP3 and Dkk1 inhibit T3-induced Wnt/beta-catenin activation and inhibit the maturation-promoting effects of T3 in growth plate cells. This study indicates that thyroid hormone regulates terminal differentiation of growth plate chondrocytes in part through modulating Wnt/beta-catenin signaling. Thyroid hormone is a potent regulator of skeletal maturation in the growth plate, yet the molecular mechanisms underlying this profound effect remain unknown. Wnt signaling has recently been recognized as an important signal transduction pathway in regulating chondrogenesis and terminal differentiation of growth plate chondrocytes. The objective of this study was to explore the interaction between the thyroid hormone and Wnt signaling pathways in the growth plate. Rat epiphyseal chondrocytes were maintained in 3D pellet culture and treated with triiodothyronine (T3). Activation of Wnt/beta-catenin signaling pathway in response to T3 was detected by measurement of the expression of Wnt-4 mRNA, the cellular accumulation of beta-catenin, the transcriptional activity of TCF/LEF, and the expression of the Wnt/beta-catenin responsive gene Runx2/cbfa1. Terminal differentiation of the chondrocytes was assessed by measurement of alkaline phosphatase enzymatic activity and Col10a1 gene expression. Thyroid hormone treatment of growth plate chondrocytes upregulated both Wnt-4 mRNA and protein expression, increased cellular accumulation of stabilized beta-catenin, increased TCF/LEF transcriptional activity, and stimulated the expression of the Runx2/cbfa1 gene. Overexpression of either Wnt-4 or a stabilized form of beta-catenin promoted growth plate chondrocyte terminal differentiation. Blocking Wnt ligand/receptor interactions with the secreted Wnt antagonists Frzb/sFRP3 or Dkk1 inhibited these T3-induced increases in beta-catenin accumulation and Runx2 gene expression and inhibited the maturation-promoting effects of T3 in growth plate cells. These data suggest that thyroid hormone regulates terminal differentiation of growth plate chondrocytes in part through modulating canonical Wnt/beta-catenin signaling.