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

描述(申请人提供)：随着我们对信号转导知识的增加，很明显，进一步的科学进步将需要了解单个信号通路如何整合到一个更广泛的信号网络中，该网络调节基本的细胞过程，如增殖和分化。五十多年前，甲状腺激素首次被确认为生长板中骨骼成熟的有力调节因素。自那时以来，许多体内外研究证实，甲状腺激素调节生长板细胞增殖和终末分化之间的关键转变，特别是生长板软骨细胞向肥大细胞的成熟。然而，这些研究既没有确定甲状腺激素调节骨骼成熟的分子机制，也没有证明甲状腺激素的全身作用如何与生长板的局部调节环境相结合。规范的Wnt信号通路最近被认为是软骨细胞成熟的另一个重要调节因子。我们实验室最近的研究表明，生长板软骨细胞经甲状腺激素处理后，典型的Wnt信号被激活，并且在甲状腺激素处理24小时内，从蛋白质中去除羧基末端精氨酸残基的Wnt调节剂--羧基肽酶Z(CPZ)的表达上调了10倍。以前的研究人员也观察到甲状腺激素对生长板生长激素和IGF-1受体表达的积极影响，以及IGF-1信号对生长板软骨细胞肥大和β-连环蛋白胞浆积累的积极影响。以下特定目的将检验甲状腺激素通过调节生长板软骨细胞的Wnt信号通路来调节骨骼成熟的新假说，并将确定这种甲状腺激素效应在多大程度上是由CPZ和/或生长激素/IGF-1(GH/IGF-1)轴介导的：1)体外和体内甲状腺激素处理对典型的Wnt信号通路关键元件的表达和活性的影响；2)确定甲状腺激素对典型的Wnt信号通路的影响程度；3)明确GH/IGF-1在多大程度上影响甲状腺激素对规范的Wnt信号的影响。

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.