Ihh and PTHrP Regulate Articular Chondrocyte Maintenance

描述（由申请人提供）：印度刺猬甲状旁腺相关蛋白（Ihh/PTHrP）轴调节生长软骨细胞分化程序（圆？平的？肥大前期？肥大的），其驱动软骨内骨发育。我们已经发现Ihh-PTHrP轴在胚胎和建立的关节软骨中也是有效的。在胚胎中，Ihh-PTHrP轴阻止新生关节的矿化。在建立的关节软骨轴调节机械负荷，PTHrP位于上游的Ihh的信号序列。 我们的工作假设是，PTHrP和Ihh参与调节建立的关节软骨的维护，我们建议在小鼠中通过条件性删除PTHrP，Ihh信号或两者来测试这一假设。在具体目标1中，我们将测试PTHrP调节关节软骨细胞分化的假设，并且在此过程中是关节软骨维持的参与者。我们将通过两个子目标来测试该想法：1）通过Gdf 5启动子有条件地缺失中间区关节软骨细胞中的PTHrP，和B）通过用设计成突出维持失调的方案（如果存在）攻击这些小鼠。在具体目标2中，我们提出通过GDF 5-Cre靶向在中间区关节软骨细胞中有条件地删除Smoothened（Smo）来测试Ihh在关节软骨维持中的假定作用。我们进一步提出研究的组合效应的轴在关节软骨细胞有条件地删除PTHrP和Smo一起。 公共卫生相关性：构成关节软骨的软骨细胞必须保持其天然的未分化状态，以便使该软骨执行其正常功能，包括润滑关节和缓冲负重关节中的负荷。当软骨细胞分化时，它们开始矿化和退化，这些是骨关节炎的标志，骨关节炎是关节炎的最常见形式，也是全球残疾的主要原因。我们在这里描述了两种调节分子，它们似乎共同调节关节软骨细胞的分化，并描述了可能在细胞和分子水平上深入了解骨关节炎病因的模型。

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.