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

描述(申请人提供)：衰老和与年龄相关的疾病，如骨关节炎(OA)，会导致关节滑液的病理变化，降低润滑功能，导致退行性磨损，通常会导致疼痛和残疾。滑膜关节由浸泡在滑液(SF)中的滑膜腔定义，滑液受到关节囊的限制，滑膜是一种纤维组织，由细胞内膜层、滑膜和松散的连接内膜下层(滑膜下层)组成。SF是血浆的超滤液，通过滑膜过滤，并由局部细胞群分泌额外的润滑剂。在正常的关节连接中，大部分SF在关节腔内移动，关节囊组织变形，尽管这些变形的幅度及其对分子运输的影响鲜为人知。虽然SF润滑剂的分泌率是机械敏感的，但关节囊的体积和局部应变大小尚未确定。滑膜和软骨的运输和分泌特性在很大程度上决定了SF润滑剂的动态平衡，以及SF在关节连接过程中提供低摩擦、低磨损的软骨-软骨滑动的能力。随着年龄的增长，关节囊组织的生物力学和运输特性发生改变。骨关节炎是一种社会和经济负担很高的衰弱关节疾病。已经描述了衰老和骨关节炎的动物模型，包括老年啮齿动物品系，关节内注射晚期糖基化终产物(AGE)随年龄积累在关节组织中的模型，以及大鼠前十字韧带切除(ACLT)手术造成的骨关节炎不稳定模型。因此，这一假说是关节囊和滑膜的力学性质随着年龄和年龄相关疾病的改变而改变，从而影响大分子物质在组织中的运输特性，并导致衰老和骨关节炎模型大鼠滑液成分的变化。拟议中的实验将首次分析三种衰老和与年龄相关疾病的大鼠模型的关节囊体积和局部菌株。此外，还将评估润滑剂分子在SF中的运输和分泌速率，以便对润滑剂的动态平衡和老化和疾病中的失调进行详细的建模分析，这些失调可能导致SF润滑性减少、软骨磨损、滑膜炎症以及润滑剂运输和损失增加，从而进一步降低SF的润滑能力。关节的隔室模型将被扩展，以允许从理论上研究疾病扰动对关节的影响，如润滑油分泌率的变化。这些结果也可能有助于确定潜在的临床干预点和策略，以逆转由于衰老和骨关节炎引起的关节病理变化。

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.