Role of the Infrapatellar Fat Pad in the Development of Post-Traumatic Osteoarthritis Following Blunt Impact to the Knee Joint

髌下脂肪垫在膝关节钝性撞击后发生创伤后骨关节炎中的作用

• 批准号: 10654180
• 负责人: John Leicester Williams
• 金额: $ 42.53万
• 依托单位: UNIVERSITY OF MEMPHIS
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-07-01 至 2026-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10654180
• 关键词: Accounting; Acute; Adipose tissue; Affect; American; Animal Model; Animals; Anterior; Appearance; Athletic Injuries; Behavior; Biochemical Pathway; Biomechanics; Blunt Trauma; Cartilage; Case Study; Cells; Cephalic; Chondrocytes; Clinical; Connective Tissue; Control Animal; Contusions; Degenerative polyarthritis; Deterioration; Development; Disease; Drops; Drug or chemical Tissue Distribution; Edema; Engineering; Excision; Failure; Fatty acid glycerol esters; Female; Femur; Fracture; Geography; Glycosaminoglycans; Goals; Health; Histopathology; Homeostasis; Inflammation; Inflammatory; Injury; Interdisciplinary Study; Intervention; Joints; Knee; Knee bone; Knee joint; Laboratories; Lateral; Ligaments; Limb structure; Link; Lower Extremity; Medial; Mediator; Meniscus structure of joint; Microcomputers; Modeling; Molecular; Operative Surgical Procedures; Oryctolagus cuniculus; Pathogenesis; Pathologic; Pathology; Pathway interactions; Patients; Play; Productivity; Property; Proteomics; Qualifying; Reporting; Research; Role; Serum; Severities; Shapes; Sports; Structure; Synovial Fluid; Testing; Time; Tissues; Training; Trauma; Traumatic Arthropathy; Work; X-Ray Computed Tomography; articular cartilage; biomechanical test; bone; calcification; cartilage cell; comparative; guinea pig model; improved; injured; joint injury; male; metabolomics; motor vehicle injury; negative affect; pressure; prevent; subchondral bone; undergraduate student

PROJECT SUMMARY Excessive compressive load caused by blunt impact to the knee, such as during a car accident or sports injury, is known to lead to osteoarthritis (OA) within the joint. Often times, no gross ligament or meniscal damage is present in these cases; given this, occult damage is not treated, representing an underserved opportunity to prevent later pathology. Our laboratory previously developed a model, using the Flemish Giant rabbit, to study the effects of impact compressive loading to the knee. This model has shown that blunt impacts result in: (i) cartilage damage; (ii) microcracks at the interface between calcified cartilage and underlying subchondral bone in the tibial plateau; and (iii) significant loss of glycosaminoglycans in the meniscal tissue, all of which point to clinical signs of post-traumatic osteoarthritis (PTOA). Interestingly, recent studies by our group using the Hartley guinea pig model of spontaneous OA have shown that early removal of the infrapatellar fat pad (IFP) was able to prevent progression of pathology (i.e. histopathology and micro-computer tomography scores were reduced in the limbs with the IFP removed compared to sham control). Improvement in limbs was attributed to the development of a replacement fibrous connective tissue (FCT) in place of the IFP, which demonstrated less evidence of inflammation and fewer changes in material properties of joint tissues than the native adipose depot. Given this, the goal of the present study is to further elucidate the role of the IFP in PTOA development in our Flemish Giant rabbit model of compressive loading. We propose to determine the role that injured IFP plays in knee degeneration and identify whether biomechanical and/or molecular pathways may be influencing the development of PTOA post-injury. We hypothesize that removal of the IFP will prevent/decrease PTOA following blunt impact to the knee. We will accomplish this via two subaims: (1) Correlate the presence and severity of PTOA to the tissue distribution of inflammatory/pathologic mediators in the joint. Proposed work will quantitate the presence of key inflammatory and matrix degrading molecules in joint tissues, serum (systemic changes), and synovial fluid (local changes) via proteomics and metabolomics. (2) Assess the biomechanical properties of the bone, cartilage, and menisci following removal of the IFP. Biomechanical properties of joint tissue will be characterized using: cranial drawer tests; tensile tests, which will evaluate the time dependent and failure properties of the whole knee joint; macro-indentation testing of articular cartilage, menisci, IFP, and FCT, which will establish the comparative stiffness of these structures; and shear and compression testing of the IFP and FCT to determine material behavior. By pursuing this mechanistic rationale to explain the negative ramifications of the IFP on knee joint health, our work may support early removal of the IFP in patients who have suffered a blunt trauma to the knee joint. Our dual approach will be helmed by a uniquely qualified research team with demonstrated productivity. Additionally, this project will train undergraduates in multi-disciplinary research ranging from molecular mechanisms to engineering.

项目摘要 由于对膝盖的钝性冲击而导致的过度压缩负荷，例如在车祸或运动损伤期间， 已知会导致关节内的骨关节炎（OA）。通常情况下，没有严重的韧带或踝关节损伤， 存在于这些情况下;鉴于此，隐匿性损伤没有得到治疗，代表了一个服务不足的机会， 防止以后的病理。我们的实验室以前开发了一个模型，使用佛兰芒巨兔，研究 冲击压缩负荷对膝关节的影响。该模型表明，钝头撞击导致： 软骨损伤;（ii）钙化软骨和底层软骨下骨之间界面处的微裂纹 胫骨平台;和（iii）关节组织中糖胺聚糖的显著损失，所有这些都表明 创伤后骨关节炎（PTOA）的临床体征。有趣的是，我们小组最近的研究使用哈特利 自发性OA豚鼠模型显示，早期去除髌下脂肪垫（IFP）能够 预防病理学进展（即组织病理学和微型计算机断层扫描评分降低 与假手术对照相比，在去除IFP的肢体中）。四肢的改善归因于 替代纤维结缔组织（FCT）代替IFP的发展， 炎症的证据和关节组织的材料性质的变化比天然脂肪库少。 鉴于此，本研究的目标是进一步阐明IFP在我们的PTOA发展中的作用。 Flemish Giant兔压缩负荷模型。我们建议确定受伤的IFP在 膝关节退行性变，并确定生物力学和/或分子途径是否可能影响 损伤后PTOA的发展。我们假设移除IFP将预防/减少PTOA 膝盖受到钝器撞击后死亡我们将通过两个子目标来实现这一点：（1）将存在和 PTOA的严重程度与关节中炎症/病理介质的组织分布有关。拟议工作将 定量关节组织、血清（全身性）和/或关节周围组织中关键炎症和基质降解分子的存在， 变化）和滑液（局部变化）。(2)评估生物力学 去除IFP后骨、软骨和骨小梁的性质。关节生物力学特性 将使用以下方法表征组织：颅骨抽屉试验;拉伸试验，其将评价时间依赖性， 整个膝关节的失效特性;关节软骨、膝关节软骨、IFP和FCT的宏观压痕测试， 这将确定这些结构的相对刚度;以及IFP的剪切和压缩测试 和FCT来确定材料行为。通过追求这种机械的基本原理来解释消极的 IFP对膝关节健康的影响，我们的工作可能会支持IFP患者的早期切除， 膝关节遭受了钝伤我们的双重方法将由一个独特的合格的研究团队掌舵 并展示了生产力。此外，本项目还将培养大学生进行多学科研究的能力 从分子机制到工程学。