WNT PROTEINS IN ADULT, AGED AND OSTEOARTHRITIC CARTILAGE

成人、老年和骨关节炎软骨中的 WNT 蛋白质

• 批准号: 6828411
• 负责人: KAREN E YATES
• 金额: $ 8.65万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-08-15 至 2006-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6828411
• 关键词: adult human (21+); age difference; biological signal transduction; biomechanics; cartilage development; chondrocytes; clinical research; disease /disorder proneness /risk; extracellular matrix proteins; gene expression; human old age (65+); human tissue; immunocytochemistry; mucopolysaccharides; osteoarthritis; polymerase chain reaction; posttranslational modifications; protein structure function; proteoglycan; recombinant proteins; sulfation; tissue /cell culture

DESCRIPTION (provided by applicant): Age-associated changes in cartilage matrix alter its ability to provide pain-free joint movement. Changes in matrix proteoglycans affect cartilage biomechanics, making aged tissue more susceptible to damage. Indeed, age is the major risk factor for osteoarthritis (OA), a chronic degenerative condition that affects ~20 million people in the US. This project tests the hypothesis that Wnt family proteins regulate cartilage matrix synthesis, and that this function is altered in old age and in OA. This hypothesis is synthesized from two well-established lines of evidence: 1) Cartilage matrix glycosaminoglycan (GAG) content, structure, and sulfation change with age and OA, and 2) The amount and sulfation of matrix GAGs influence Wnt signaling and expression. Additional evidence to support our hypotheses is that nuclear b-catenin, an indicator of Wnt signaling, is found in adult cartilage, and our Preliminary Studies show expression of many Wnt ligands, receptors, signaling and target genes in adult chondrocytes. Wnt proteins have also been shown to regulate matrix synthesis by chondrogenic cells in vitro. The proposed studies will use human articular chondrocytes isolated from discarded tissues of patients undergoing total knee replacement. Specific Aim l is to define the Wnt component expression profile of adult chondrocytes (30-50 years), and compare it to aged (>70 years) and OA chondrocytes. Specific Aim II is to investigate the link between Wnt signaling and chondrogenesis, and determine whether this is decreased in aged and OA chondrocytes. Our results will have a significant impact on understanding mechanisms of normal and pathologic aging of cartilage, and may lead to novel therapeutic and preventative strategies to rejuvenate cartilage. This work will also provide a solid foundation for future research on Wnts in cartilage biology.

描述（由申请人提供）：软骨基质的年龄相关变化改变了其提供无疼痛关节运动的能力。基质蛋白聚糖的变化会影响软骨生物力学，使老化的组织更容易受到损害。确实，年龄是骨关节炎（OA）的主要危险因素，这是一种慢性退化疾病，影响了美国约2000万人。该项目检验了Wnt家族蛋白调节软骨基质合成的假设，并且该功能在老年和OA中发生了变化。该假设是从两条公认的证据线中综合的：1）软骨基质糖胺聚糖（GAG）含量，结构和硫酸化随着年龄和OA的变化而变化，以及2）矩阵GAGS的量和硫化影响Wnt信号和表达。支持我们假设的其他证据是，在成人软骨中发现了核B-catenin，这是Wnt信号传导的指标，我们的初步研究表明，成人软骨细胞中许多Wnt配体，受体，信号和靶基因的表达。 Wnt蛋白还显示出在体外由软骨细胞调节基质合成的。拟议的研究将使用从接受总膝关节置换的患者的废弃组织中分离出的人类关节软骨细胞。具体目的L是定义成年软骨细胞（30 - 50年）的Wnt成分表达谱，并将其与老化（> 70年）和OA软骨细胞进行比较。具体目的II是研究Wnt信号传导与软骨生成之间的联系，并确定在老年和OA软骨细胞中是否会减少。我们的结果将对软骨正常和病理老化的机制产生重大影响，并可能导致新颖的治疗和预防策略使软骨恢复活力。这项工作还将为未来关于软骨生物学WNT的研究提供坚实的基础。