Joint Capsule Biomechanics and Transport in Rat Models of Aging and Disease

描述（由申请人提供）：衰老和年龄相关疾病，如骨关节炎（OA），导致关节滑液发生病理变化，降低润滑功能，导致退行性磨损，通常导致疼痛和残疾。滑膜关节由浸泡在润滑性滑液（SF）中的滑膜腔定义，该滑液受到关节囊的限制，关节囊是由细胞内膜层（滑膜）和疏松结缔内膜下层（滑膜下层）组成的纤维组织。SF是通过滑膜过滤的血浆超滤液，具有由局部细胞群分泌的额外润滑剂。在正常的关节连接过程中，大部分SF在关节腔内移位，关节囊组织变形，尽管对这些变形的大小及其对分子转运的影响知之甚少。关节囊的体积和局部应变大小尚未确定，但SF润滑剂的分泌速率已知是机械敏感的。滑膜和软骨的运输和分泌特性在决定SF润滑剂稳态和SF在关节接合期间提供低摩擦、低磨损软骨对软骨滑动的能力方面起着重要作用。关节囊组织的生物力学和运输特性在衰老和OA中改变，OA是一种具有高社会和经济负担的衰弱性关节疾病。已经描述了衰老和OA的动物模型，包括老年啮齿动物品系、关节组织中晚期糖基化终产物（AGE）随年龄积累的关节内核糖注射模型和大鼠中OA的前交叉韧带损伤（ACLT）手术失稳模型。因此，该提议的假设是关节囊和滑膜的机械特性随着年龄和年龄相关疾病而改变，影响大分子通过组织的运输特性，并导致衰老和OA大鼠模型中滑液组成的变化。拟议的实验将提供第一次分析关节囊体积和局部应变在三个大鼠模型的衰老和年龄相关疾病。此外，还将评估SF中润滑剂分子的运输和分泌速率，从而对润滑剂稳态以及可能导致SF润滑性降低、软骨磨损、滑膜炎症以及润滑剂运输和损失增加（导致SF润滑能力进一步降低）的衰老和疾病中的失调进行详细建模分析。将扩展关节的房室模型，以允许对疾病扰动对关节的影响进行理论研究，例如改变润滑剂分泌速率。这些结果也可能是有用的，在确定潜在的临床干预点和策略，以扭转病理性关节变化，由于老化和OA。 公共卫生相关性：衰老和与年龄相关的疾病，如骨关节炎，导致关节滑液的病理变化，降低润滑功能，导致退行性磨损，并经常导致疼痛和残疾。该项目的目标是通过确定关节囊生物力学和润滑剂分子运输和分泌速率，更好地了解和模拟健康和病理性滑液润滑剂分子稳态。研究结果将提高我们对关节老化和骨关节炎变化的理解，并有助于确定潜在的临床干预策略。

DESCRIPTION (provided by applicant): Aging and age-related diseases, such as osteoarthritis (OA), result in pathological changes to the synovial fluid in joints, reducing lubrication function and leading to degenerative wear and often to pain and disability. Synovial joints are defined by a synovial cavity bathed in lubricating synovial fluid (SF) that is constrained by the joint capsule, a fibrous tissue consisting of a cellular intimal layer, the synovium, and a loose connective sub-intimal layer, the subsynovium. SF is an ultrafiltrate of plasma, filtered through synovium, with additional lubricants secreted by local cell populations. During normal joint articulation, the bulk of the SF shifts within the joint cavity and joint capsule tissue deforms, though little is known about the magnitude of these deformations and their effect on molecular transport. The volumetric and local strain magnitudes of joint capsule have not been determined, though the secretion rates of SF lubricants are known to be mechanosensitive. The transport and secretion characteristics of synovium and cartilage play a large role in determining SF lubricant homeostasis and the ability of SF to provide low-friction, low-wear cartilage-on- cartilage sliding during joint articulation. The biomechanical and transport characteristics of joint capsule tissue are altered in aging and in OA, a debilitating joint disease with a high social and economic burden. Animal models of aging and OA have been described, including aged rodent strains, an intraarticular ribose injection model of advanced glycation end-product (AGE) accumulation in joint tissues with age, and an anterior cruciate ligament transaction (ACLT) surgical destabilization model of OA in rats. Thus, the hypothesis of this proposal is that the mechanical properties of joint capsule and synovium are altered with age and age-related disease, affecting the transport characteristics of macromolecules through the tissue, and contributing to changes in synovial fluid composition in rat models of aging and OA. The proposed experiments will provide the first analysis of joint capsule volumetric and local strains in three rat models of aging and age-related disease. In addition, the transport and secretion rates of lubricant molecules in SF will be assessed, allowing a detailed modeling analysis of lubricant homeostasis and the dysregulation in aging and disease that likely contributes to decreased SF lubrication, cartilage wear, synovium inflammation, and increased lubricant transport and loss, which leads to further decreased SF lubricating ability. A compartmental model of the joint will be extended to allow for theoretical investigation of the effects of disease perturbations on the joint, such as altered lubricant secretion rates. These results may also be useful in identifying potential clinical intervention points and strategies to reverse pathological joint changes due to aging and OA. PUBLIC HEALTH RELEVANCE: Aging and age-related diseases, such as osteoarthritis, result in pathological changes to the synovial fluid in joints, reducing lubrication function and leading to degenerative wear and often to pain and disability. The goals of this project are to better understand and model healthy and pathological synovial fluid lubricant molecule homeostasis by determining joint capsule biomechanics and lubricant molecule transport and secretion rates. The results will improve our understanding of aging and osteoarthritic changes in joints and help identify potential clinical intervention strategies.