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

描述（由申请人提供）：随着我们对信号转导的了解的增加，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调节基本细胞过程（如增殖和分化）的更广泛的信号网络中。50多年前，甲状腺激素首次被确定为生长板骨骼成熟的有效调节剂。从那时起，许多体外和体内研究已经证实，甲状腺激素调节生长板中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成熟为肥大细胞。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互作用。经典的Wnt信号通路最近被确定为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，典型的Wnt信号被甲状腺激素处理的生长板软骨细胞激活，羧肽酶Z（CPZ），一种Wnt调节剂，从蛋白质中去除羧基末端精氨酸残基，在甲状腺激素处理的24小时内上调10倍。以前的研究人员也观察到甲状腺激素对生长板中生长激素和IGF-1受体表达的积极作用，以及IGF-1信号传导对β-连环蛋白的细胞质积累和生长板软骨细胞肥大的积极作用。以下具体目的将检验甲状腺激素通过调节生长板软骨细胞中的Wnt信号通路来调节骨骼成熟的新假设，并将确定这种甲状腺激素效应由CPZ和/或生长激素/ IGF- 1介导的程度（GH/IGF-1）轴：第一章确定甲状腺激素处理生长板软骨细胞对经典Wnt信号通路关键元件的表达和活性的影响体外和体内; 2）确定CPZ介导的甲状腺激素对经典Wnt信号传导的影响程度; 3）确定GH/IGF-1介导的甲状腺激素对经典Wnt信号传导的影响程度。

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.