Role of cartilage matrix in a model of load-induced OA

描述（由申请人提供）：本申请涉及衰老中骨关节炎介导机制PA-12-018的计划公告。我们的重点是了解机械生物学因素在骨关节炎的发病和进展中的作用，在小鼠模型与受损的组织特性。骨关节炎（OA）通过改变受影响关节的结构和性质，特别是软骨和骨的结构和性质，降低活动性和功能。生物学和机械因素都与OA的发展和发作有关，包括机械负荷。我们已经开发了小鼠膝关节的非侵入性体内小鼠负荷模型，该模型在时间和解剖学上再现了临床OA样特征。将该模型与转基因小鼠相结合，我们计划使用在3个月龄时自发形成早期OA样特征的转基因小鼠来研究软骨组成改变在OA发展中的作用。我们假设，与野生型同窝小鼠相比，软骨基质组成和性质异常的小鼠膝关节的受控机械负荷将导致关节软骨和关节周围骨中OA样变化增强。为了确定负荷是否加速OA样变化的发展，我们将在3月龄和6月龄时将具有Xi型单倍性不足的小鼠（cho/+小鼠）与野生型对照进行比较，并施加1、2和6周的负荷。将通过组织学、显微计算机断层扫描、免疫组织化学、RT-qPCR、原子力显微镜和运动学分析评估软骨、骨和关节活动度的变化。这种负荷模型提供了一个机会，研究机械刺激的反应，没有并发关节创伤，以更好地了解机械因素的OA和关节退行性变的生物和机械因素的相互作用。

DESCRIPTION (provided by applicant): This application addresses the program announcement for Mechanisms Mediating Osteoarthritis in Aging PA-12-018. Our focus is on understanding the role of mechanobiological factors in the onset and progression of osteoarthritis in a mouse model with compromised tissue properties. Osteoarthritis (OA) reduces mobility and function by altering the structure and property of the affected joint, particularly of the cartilage and bone. Both biological and mechanical factors have been linked to the development and onset of OA, including mechanical loading. We have developed non-invasive in vivo mouse loading model of the mouse knee that recapitulates clinical OA-like features temporally and anatomically. Combining this model with transgenic mice, we plan to investigate the role of altered cartilage composition in the development of OA using transgenic mice that spontaneously develop early OA-like features at 3 months of age. We hypothesize that controlled mechanical loading of the knee joints in mice with abnormal cartilage matrix composition and properties will result in enhanced OA-like changes in articular cartilage and peri-articular bone compared to their wild type littermates. To determine whether loading expedites the development of OA-like changes, we will compare mice with type XI haploinsufficiency (cho/+ mice) to wild-type controls at 3 and 6 months of age and apply 1, 2 and 6 weeks of loading. Changes in cartilage, bone and joint mobility will be assessed by histology, microcomputed tomography, immunohistochemistry, RT-qPCR, atomic force microscopy, and kinematic analysis. This loading model provides an opportunity to study the response to mechanical stimuli without concurrent joint trauma to better understand mechanical factors contributing to OA and the interaction of biological and mechanical factors in joint degeneration.