Ihh and PTHrP Regulate Articular Chondrocyte Maintenance

描述(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计划(轮？没气吗？肥大前期？肥大性)，驱动软骨内骨发育。我们发现IHH-PTHrP轴在胚胎和已建立的关节软骨中也是可操作的。在胚胎中，IHH-PTHrP轴阻止新生关节的矿化。在已建立的关节软骨中，轴由机械负荷调节，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有条件地删除PTHrP和IHH信号或两者兼而有之来检验这一假设。在特定的目标1中，我们将检验PTHrP调节关节软骨细胞分化的假设，并在此过程中参与关节软骨的维护。我们将通过两个子目标来测试这一想法：1)通过GDF5启动子有条件地删除中区关节软骨细胞中的PTHrP；b)通过一种旨在强调维持失调的方案(S)挑战这些小鼠(如果存在)。在特定的目标2中，我们建议通过GDF5-Cre靶向有条件地删除中带关节软骨细胞中的Smoothens(Smo)来测试IHH在关节软骨维持中的可能作用。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效应。 与公共健康相关：构成关节软骨的软骨细胞必须保持其天然的、未分化的状态，以便该软骨执行其正常功能，包括润滑关节和缓冲承重关节的负荷。当软骨细胞分化时，它们开始矿化和退化，这是骨关节炎的特征，骨关节炎是最常见的关节炎形式，也是全世界导致残疾的主要原因。我们在这里描述了两个似乎共同调节关节软骨细胞分化的调节分子，并描述了可能在细胞和分子水平上提供对骨关节炎病因的洞察的模型。

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.