The Interaction of Thyroid Hormone and Wnt Signaling Pathways in the Growth Plate

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DESCRIPTION (provided by applicant): As our knowledge of signal transduction has increased, it has become apparent that further scientific advances will require understanding of how individual signaling pathways become integrated into a broader signaling network that regulates fundamental cellular processes such as proliferation and differentiation. Thyroid hormone was first identified as a potent regulator of skeletal maturation at the growth plate more than fifty years ago. Since that time, many in vitro and in vivo studies have confirmed that thyroid hormone regulates the critical transition between cell proliferation and terminal differentiation in the growth plate, specifically the maturation of growth plate chondrocytes into hypertrophic cells. However these studies have neither identified the molecular mechanisms involved in the regulation of skeletal maturation by thyroid hormone, nor demonstrated how the systemic actions of thyroid hormone interface with the local regulatory milieu of the growth plate. The canonical Wnt signaling pathway has recently been identified as another important regulator of chondrocyte maturation. Recent studies in our laboratory indicate that canonical Wnt signaling is activated by thyroid hormone treatment of growth plate chondrocytes, and that carboxypeptidase Z (CPZ), a Wnt modulator that removes carboxy-terminal arginine residues from proteins, is upregulated ten-fold within 24 hours of thyroid hormone treatment. Previous investigators have also observed a positive effect of thyroid hormone on expression of the growth hormone and IGF-1 receptors in the growth plate, as well as positive effects of IGF-1 signaling on both cytoplasmic accumulation of beta-catenin and hypertrophy of growth plate chondrocytes. The following specific aims will test the novel hypothesis that thyroid hormone regulates skeletal maturation through modulation of Wnt signaling pathways in growth plate chondrocytes, and will define the degree to which this thyroid hormone effect is mediated by CPZ and/or the growth hormone / IGF- 1 (GH/IGF-1) axis: 1) To determine the effect of thyroid hormone treatment of growth plate chondrocytes on the expression and activity of key elements of the canonical Wnt signaling pathway in vitro and in vivo; 2) To define the degree to which the thyroid hormone effect on canonical Wnt signaling is mediated by CPZ; 3) To define the degree to which the thyroid hormone effect on canonical Wnt signaling is mediated by GH/IGF-1.