Fate mapping and signaling pathways of superficial cells in articular cartilage

描述(申请人提供)：骨性关节炎是一种关节软骨的退行性疾病，一种覆盖人体所有关节表面的组织。据估计，美国有2070万成年人患有这种疾病。这种疾病与剧烈的疼痛和受影响的关节活动受限有关。在成人中，关节软骨被认为是一个不更新的细胞群。然而，最近有研究表明，关节软骨表面细胞独特地表达了分泌的润滑素蛋白，在发育过程中可能为关节软骨祖细胞提供来源，可能在成人中也是如此。关节软骨由浅层、中层和深层软骨细胞组成，表现出不同的基因表达模式。这些不同的软骨细胞带之间有什么关系？浅层关节软骨细胞能长出深层细胞吗？在浅表区软骨细胞中，维持增殖、活性和润滑素表达所必需的信号是什么？在这项建议中，我概述了检验表层软骨细胞是否产生局限于表层的子代细胞和/或在关节软骨深层产生子代细胞的实验。此外，我建议确定肌肉运动和运动是否会增加关节软骨的厚度，从而促进表层关节软骨细胞或其后代的增殖。最后，我建议确定Notch和Wnt信号在维持表面区软骨细胞的增殖、活性和/或分化表型中的作用。我希望，对负责关节软骨形成和维持的前体细胞以及维持浅层软骨细胞增殖、活性和/或分化表型所需的信号的更好了解，将最终导致治疗试剂的开发，以在骨关节炎期间恢复该组织。 公共卫生意义：骨性关节炎是一种关节软骨退行性疾病。我们将在体内研究关节软骨表面细胞是否包括成人关节软骨的祖细胞群，并将确定Notch和/或Wnt信号通路是否在这些细胞的维持和/或扩增中发挥作用。识别负责维持关节表层软骨细胞层的前体细胞和信号通路，可能为骨关节炎期间修复这一组织提供治疗性的见解。

DESCRIPTION (provided by applicant): Osteoarthritis is a degenerative disease of the articular cartilage, a tissue that covers the surface of all articulating joints in the human body. It is estimated that 20.7 million adults in the US have the disease. The disease is associated with severe pain and limited movement of the affected joints. In the adult, articular cartilage was thought to be a non-renewing cell population. Recently however, it has been suggested that superficial cells of the articular cartilage, which uniquely express the secreted protein lubricin, may provide a source for articular cartilage progenitors during development and possibly in the adult. Articular cartilage consists of superficial, intermediate and deep zone chondrocytes, which display different patterns of gene expression. What is the relationship between these differing chondrocyte zones? Do superficial zone articular chondrocytes give rise to deeper zone cells? What signals are necessary to maintain proliferation, viability and lubricin expression specifically in superficial zone chondrocytes? In this proposal, I outline experiments to examine whether superficial zone chondrocytes give rise to progeny cells restricted to the superficial zone and/or give rise to progeny cells in deeper layers of articular cartilage. In addition, I propose to determine whether muscular movement and exercise, which has been noted to increase the thickness of articular cartilage augments the proliferation of either superficial zone articular cartilage cells or their progeny. Lastly, I propose to determine the role of both Notch and Wnt signaling in maintaining either the proliferation, viability and/or differentiated phenotype of superficial zone chondrocytes. It is my hope that a better understanding of both the progenitor cells that are responsible for the formation and maintenance of the articular cartilage and the signals required to maintain the proliferation, viability and/or differentiated phenotype of superficial zone chondrocytes will eventually lead to the development of therapeutic reagents to restore this tissue during osteoarthritis. PUBLIC HEALTH RELEVANCE: Osteoarthritis is a degenerative disease of the articular cartilage. We will investigate in vivo if superficial cells of the articular cartilage comprise a progenitor cell population for the articular cartilage in the adult and will determine whether the Notch and/or Wnt signaling pathways play a role in either the maintenance and/or expansion of these cells. Identification of the progenitor cells and signaling pathways that are responsible for maintenance of the superficial articular cartilage cell layer may provide a therapeutic insight into restoring this tissue during osteoarthritis.