Ihh and PTHrP Regulate Articular Chondrocyte Maintenance

Ihh 和 PTHrP 调节关节软骨细胞的维持

• 批准号: 8013499
• 负责人: Arthur Eastwood Broadus
• 金额: $ 17.87万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-01-15 至 2011-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8013499
• 关键词: Arthritis; Bone Development; Cartilage; Chondrocytes; Degenerative polyarthritis; Embryo; Erinaceidae; Functional disorder; GDF5 gene; Genes; Growth; Joints; Maintenance; Mechanics; Modeling; Molecular; Mus; Pathway interactions; Peptide Signal Sequences; Protocols documentation; Role; Signal Transduction; Testing; Undifferentiated; Weight-Bearing state; Work; articular cartilage; combinatorial; design; disability; human SMO protein; insight; mineralization; parathyroid hormone-related protein; prevent; programs; promoter; public health relevance

DESCRIPTION (provided by applicant): The Indian hedgehog-parathyroid hormone-related protein (Ihh/PTHrP) axis regulates the growth chondrocyte differentiation program (round ? flat ? prehypertrophic ? hypertrophic) that drives endochondral bone development. We have found that the Ihh-PTHrP axis is operative also in embryonic and in established articular cartilage. In the embryo, the Ihh-PTHrP axis prevents mineralization of the nascent joint. In established articular cartilage the axis is regulated by mechanical loading, with PTHrP lying upstream of Ihh in the signaling sequence. Our working hypothesis is that PTHrP and Ihh are involved in regulating the maintenance of established articular cartilage, and we propose to test this hypothesis by conditional deletion of PTHrP, Ihh signaling, or both in mice. In Specific Aim 1, we will test the hypothesis that PTHrP regulates the differentiation of articular chondrocytes and in so doing is a player in articular cartilage maintenance. We will test this idea via two sub-aims: 1) by conditionally deleting PTHrP in mid-zone articular chondrocytes via the Gdf5 promoter and b) by challenging these mice with a protocol(s) designed to highlight dysregulation of maintenance, if present. In Specific Aim 2, we propose to test the putative role of Ihh in articular cartilage maintenance by conditionally deleting Smoothened (Smo) in mid-zone articular chondrocytes via GDF5-Cre targeting. We further propose to study the combinatorial effects of the axis in articular chondrocytes by conditionally deleting PTHrP and Smo together. PUBLIC HEALTH RELEVANCE: The chondrocytes that make up articular cartilage must remain in their native, undifferentiated state in order for this cartilage to carry out its normal functions, which include lubricating the joints and cushioning load in weight-bearing joints. When chondrocytes differentiate, they begin to mineralize and degenerate, and these are hallmarks of osteoarthritis, the most common form of arthritis, and a leading cause of disability worldwide. We describe here two regulatory molecules that together seem to regulate articular chondrocyte differentiation and describe models that may provide insight into the cause of osteoarthritis at a cellular and molecular level.

描述（由申请人提供）：印度刺猬-甲状旁腺激素相关蛋白（Ihh/PTHrP）轴调节生长软骨细胞分化程序(圆形？平吗?prehypertrophic吗?肥大)驱动软骨内骨发育。我们发现Ihh-PTHrP轴在胚胎和成熟的关节软骨中也有效。在胚胎中，Ihh-PTHrP轴阻止新生关节的矿化。在成熟的关节软骨中，轴受机械负荷调节，PTHrP在信号序列中位于Ihh的上游。我们的工作假设是PTHrP和Ihh参与调节已建立的关节软骨的维持，我们建议在小鼠中通过条件删除PTHrP， Ihh信号或两者来验证这一假设。在具体目标1中，我们将验证PTHrP调节关节软骨细胞分化的假设，并在关节软骨维持中发挥作用。我们将通过两个子目标来验证这一想法：1)通过Gdf5启动子有条件地删除中间区关节软骨细胞中的PTHrP； b)用一种旨在突出维持失调（如果存在）的方案挑战这些小鼠。在Specific Aim 2中，我们提议通过GDF5-Cre靶向，有条件地删除关节软骨中间区Smoothened (Smo)，来测试Ihh在关节软骨维持中的假定作用。我们进一步建议通过有条件地同时删除PTHrP和Smo来研究轴在关节软骨细胞中的组合作用。