Kinetic Biomarkers of Joint Space Molecules in OA

描述(申请人提供)：老化导致关节软骨的组成和功能发生变化。本研究的重点是描述透明关节软骨基质和滑液成分随年龄和骨性关节炎(OA)周转(合成和降级)的变化。在最终的分析中，是基质合成和/或降解调节的失衡导致关节软骨的丢失并导致骨关节炎(1-4)。该项目的总体目标是开发和验证啮齿动物关节软骨和滑液糖胺聚糖(GAG)、胶原或胶原蛋白衍生多肽和软骨细胞在体内的周转率的动力学分析(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。 具体来说，我们的目标是 (1)建立稳定的同位素/质谱法测定大鼠关节软骨和关节滑液中透明质酸(HA)和硫酸氯化铁(CS)的转化率。 (2)建立稳定的同位素/质谱法测定大鼠关节软骨胶原和滑液胶原衍生肽的周转率，并建立一种新的关节软骨胶原和滑液胶原衍生肽模型。 (3)探讨大鼠和豚鼠关节软骨细胞增殖随年龄和骨性关节炎的变化。 (4)比较不同采样部位(关节软骨、滑膜液浆)对关节保护性生化成分(GAG‘s胶原蛋白及其分解产物、软骨细胞)的动态测量，以了解和解释这些动态生物标志物的变化。 (5)比较上述关节保护成分在豚鼠模型中的动态变化与骨性关节炎的组织学和静态生化指标。综上所述，我们建议开发和测试关节间隙的主要保护成分(GAG、胶原和软骨细胞)的动态生物标记物，并将这些指标与OA的组织学标记物相关联。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了解取得重大进展，并有可能应用于关节疾病的预防和治疗。

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.