Kinetic Biomarkers of Joint Space Molecules in OA

描述（由申请人提供）：老化导致关节软骨的组成和功能发生变化。本研究的重点是表征透明关节软骨基质和滑液成分随年龄和骨关节炎（OA）的周转（合成和降解）变化。在最终分析中，是基质合成和/或降解调节的失衡导致关节软骨丢失并导致OA（1-4）。本项目的总体目标是开发和验证啮齿动物体内关节软骨和滑液糖胺聚糖（GAG）、胶原蛋白或胶原蛋白衍生肽和软骨细胞周转率的动力学测定（动力学生物标志物），以最终用于OA的药物开发、临床试验和患者护理。 具体而言，我们的目标是 (1)评价一种新开发的稳定同位素/质谱方法，用于测量大鼠和OA动物模型（衰老豚鼠）中GAG透明质酸（HA）和硫酸软骨素（CS）的关节软骨和滑液周转率。 (2)评价一种新开发的稳定同位素/质谱方法，用于测量大鼠和OA动物模型（衰老豚鼠）中关节软骨胶原和滑液胶原衍生肽的周转率。 (3)评价大鼠和豚鼠软骨细胞增殖随年龄和OA的变化。 (4)比较来自不同取样部位（关节软骨、滑液血浆）的这些关节保护性生化成分（GAG胶原及其分解产物、软骨细胞）的动力学测量结果，以了解和解释这些动力学生物标志物的变化。 (5)在豚鼠模型中比较这些关节保护成分的动力学测量与OA的组织学和静态生化标志物。总之，我们建议开发和测试关节间隙主要保护成分（GAG、胶原和软骨细胞）的动力学生物标志物，并将这些指标与OA的组织学标志物相关联。这些工具可能使我们对关节间隙细胞外基质生物学的基本理解取得重大进展，并可能应用于关节炎疾病的预防和治疗。

DESCRIPTION (provided by applicant): Aging results in changes in the composition and function of articular cartilage. The focus of this research is to characterize changes in turnover (synthesis and degredation) of components of hyaline articular cartilage matrix and synovial fluid with age and osteoarthritis (OA). In the finial analysis, it is an imbalance in the regulation of matrix synthesis and/or degradation that results in the loss of articular cartilage and leads to OA (1-4). The general objective of this project it to develop and validate kinetic assays (kinetic biomarkers) of turnover rates of articular cartilage and synovial fluid glycosaminoglycans (GAG), collagen, or collagen derived peptides and chondrocytes in vivo in rodents for ultimate use in drug development, clinical trials and patient care in OA. Specifically, our objectives are (1) to evaluate a newly developed stable isotope/ mass spectrometric method for measuring articular cartilage and synovial fluid turnover rates of the GAG's hyalurenic acid (HA) and chrondroitin-sulfate (CS) in rats and in an animal model of OA (aging guinea pigs). (2) to evaluate a newly developed stable isotope / mass spectrometric method for measuring turnover rates of articular cartilage collagen and synovial fluid collagen-derived peptides in rats and an animal model of OA (aging guinea pigs). (3) to evaluate changes in chrondrocyte cell proliferation with age and OA in the rat and guinea pig. (4) to compare kinetic measurements of these joint protective biochemical constituents (GAG's collagen and its breakdown products, chondrocytes) from different sampling sites (articular cartilage, synovial fluid plasma) in order to understand and interpret changes in these kinetic biomarkers. (5) To compare kinetic measures of these joint protective constituents to histological and static biochemical markers of OA in the guinea pig model. In summary, we propose to develop and test kinetic biomarkers of the major protective compoments of the joint space (GAG's, collagen and chrondrocytes) and to correlate these measures with histologic markers of OA. These tools may allow significant advances in our basic understanding of the biology of the extracellular matrix in the joint space, with potential application to the prevention and treatment of arthritic disorders.