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

项目总结 由钝性撞击膝盖造成的过大压缩负荷，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，没有粗大的韧带或半月板损伤 在这些情况下存在；鉴于此，隐形损害得不到治疗，这代表着一个未得到充分利用的机会 防止以后的病理。我们的实验室之前开发了一个模型，使用佛兰德巨兔来研究 冲击压缩载荷对膝关节的影响。该模型表明，钝性撞击会导致：(I) 软骨损伤；(Ii)钙化软骨与软骨下骨交界处的微裂纹 在胫骨平台；和(Iii)半月板组织中糖胺聚糖的显著丢失，所有这些都指向 创伤后骨关节炎(PTOA)的临床症状。有趣的是，我们团队最近使用哈特利 豚鼠自发性骨性关节炎模型研究表明，早期去除髌下脂肪垫(IFP)是可行的 为了防止病理进展(即组织病理学和微型计算机断层扫描评分降低 在去除IFP的四肢中，与假对照相比)。四肢的改善归功于 替代IFP的纤维结缔组织(FCT)的发展，其表现较少 关节组织的炎症迹象和材料特性的变化比本地脂肪库要少。 鉴于此，本研究的目标是进一步阐明IFP在我国PTOA发展中的作用。 佛兰德巨兔模型的压缩载荷。我们建议确定损伤的IFP在 并确定生物力学和/或分子途径是否可能影响膝关节退行性变 创伤后PTOA的发展。我们假设移除IFP将防止/减少PTOA 在膝盖受到钝器撞击后。我们将通过两个子目标来实现这一点：(1)将存在和 PTOA的严重程度对关节内炎症/病理介质的组织分布有影响。拟议的工作将 定量检测关节组织、血清(全身)中关键炎症和基质降解分子的存在 改变)，以及滑液(局部改变)通过蛋白质组学和代谢组学。(2)生物力学评价 去除IFP后的骨、软骨和半月板的特性。关节的生物力学特性 组织的特征将使用：颅骨抽屉试验；拉伸试验，这将评估时间依赖性和 全膝关节的破坏特性；关节软骨、半月板、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。通过追求这种机械论的理由来解释消极的 IFP对膝关节健康的影响，我们的工作可能支持对患有以下疾病的患者尽早移除IFP 膝关节受到钝性创伤。我们的双重方法将由一个独一无二的合格研究团队负责 并证明了其工作效率。此外，该项目还将培训本科生进行多学科研究。 从分子机制到工程学。

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.