Fate mapping and signaling pathways of superficial cells in articular cartilage

描述（由申请人提供）：骨关节炎是关节软骨的退行性疾病，关节软骨是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。该病伴有剧烈疼痛和受影响关节活动受限。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，关节软骨的表层细胞独特地表达分泌的蛋白润滑素，可能是关节软骨在发育期间和成年后形成祖细胞的来源。关节软骨由浅层软骨细胞、中间软骨细胞和深层软骨细胞组成，它们表现出不同的基因表达模式。这些不同的软骨细胞区之间有什么关系？浅带关节软骨细胞会产生深带细胞吗？哪些信号是维持浅表带软骨细胞增殖、活力和润滑素表达所必需的？在本提案中，我概述了实验，以检查是否浅层软骨细胞产生限于浅层的后代细胞和/或产生关节软骨更深层的后代细胞。此外，我建议确定肌肉运动和锻炼是否会增加关节软骨的厚度，从而增加浅层关节软骨细胞或其后代的增殖。最后，我建议确定Notch和Wnt信号在维持浅表带软骨细胞增殖、活力和/或分化表型中的作用。我希望更好地了解负责关节软骨形成和维持的祖细胞，以及维持浅层软骨细胞增殖、活力和/或分化表型所需的信号，最终将导致治疗试剂的发展，以恢复骨关节炎期间的组织。

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.