Biomarkers of Cartilage Metabolism and OA

描述（由申请人提供）：关于骨关节炎（OA）的大多数已知信息来自于专注于该疾病后期的临床研究，对其发病和早期进展知之甚少，并且在诊断时，存在疼痛和不可修复的软骨损伤。产生OA发病的机制尚不清楚，需要时间才能取得进展，并且测量关节软骨生物力学和生物学行为早期变化所需的工具最近才变得可用。本研究将是一项病例对照研究，研究对象为一组相对同质的受试者，这些受试者可在首次前交叉韧带（ACL）创伤时确定，并且具有创伤后OA发作的显著风险。本研究的主要目的是测量从滑液样本和关节间隙宽度狭窄（OA进展的有效指标）中获得的关节软骨代谢生物标志物浓度的时间变化。这些测量将在术前计划接受ACL重建的受试者和招募时膝关节正常的匹配对照受试者中进行。将在12个月、24个月和48个月的随访间隔时重复测量。这些数据将用于检验主要假设：关节软骨代谢的滑液生物标志物水平（选择用于评价II型胶原和蛋白聚糖）与胫股关节间隙狭窄相关。ACL的破坏导致前后（A-P）膝关节松弛、关节不稳定的急剧增加，尽管该韧带的重建试图重建正常的关节生物力学，但它通常导致愈合期间A-P膝关节松弛的异常增加。ACL损伤和重建导致OA的一种机制可以通过一种自我延续的过程来解释，其中ACL移植物内的结构变化导致A-P膝关节松弛增加、关节软骨接触应力异常、软骨代谢异常、关节软骨特性异常，并最终导致该结构的丧失。这是我们探索性假设的基础：关节软骨代谢的滑液生物标志物与胫股关节间隙狭窄之间的关系可以通过愈合期间A-P膝关节松弛度的增加来解释。这项研究很重要，因为它将验证使用滑液生物标志物研究创伤后OA的早期进展，并提供与ACL重建和OA进展相关的膝关节生物力学改变之间的关系的见解。

DESCRIPTION (provided by applicant): Most of what is known about osteoarthrits (OA) has been derived from clinical studies that have focused on the latter stages of this disease, very little is known about its onset and early progression, and by the time its diagnosed, pain and irreparable cartilage damage are present. The mechanism that produces the onset of OA is unclear, it requires time to progress, and the tools necessary to measure the early changes in the biomechanical and biological behavior of articular cartilage have only become available recently. This investigation will be a case-control study of a relatively homogenous group of subjects that can be identified at the time of index anterior cruciate ligament (ACL) trauma and are at significant risk for the post-traumatic onset of OA. The primary aim of the study will be to measure the temporal changes in the concentrations of the biomarkers of articular cartilage metabolism obtained from synovial fluid samples and joint space width narrowing (a validated indicator of progression of OA). These measurements will be made in subjects that plan to undergo ACL reconstruction immediately before surgery, and in matched control subjects with normal knees at the time of recruitment. Measurements will be repeated at the follow-up intervals of 12, 24, and 48-months. These data will be used to test the primary hypothesis: synovial fluid biomarker levels of articular cartilage metabolism (selected to evaluate Type II collagen and proteoglycan) are associated with narrowing of the tibiofemoral joint space. Disruption of the ACL leads to a dramatic increase in anterior-posterior (A-P) knee laxity, joint instability, and although reconstruction of this ligament attempts to re-establish normal joint biomechanics, it often results in an abnormal increase of A-P knee laxity during healing. One mechanism by which ACL injury and reconstruction leads to OA may be explained by a self-perpetuating process in which structural changes within the ACL graft produce increases in A-P knee laxity, abnormal articular cartilage contact stress, abnormal cartilage metabolism, abnormal articular cartilage properties, and eventually loss of this structure. This serves as the basis for our exploratory hypothesis: the relationship between synovial fluid biomarkers of articular cartilage metabolism and narrowing of the tibiofemoral joint space can be explained by increases in A-P knee laxity during healing. This investigation is important because it will validate the use of synovial fluid biomarkers for the study of early progression of post-traumatic OA and provide insight into the relationship between the altered knee biomechanics associated with ACL reconstruction and progression of OA.