The Role of Fat in Osteoarthritis

项目摘要 骨关节炎（OA）是全球范围内疼痛和残疾的主要原因，目前没有疾病 可用的修改治疗。虽然肥胖诱导的OA涉及代谢和生物力学因素， 关键环节是多余的脂肪，或脂肪组织-炎症介质的来源，涉及的发病机制， OA。肥胖、生物力学改变和代谢综合征的机制影响已经被 难以确定和解开。为了分离这些因素，我们使用了脂肪营养不良（LD）的小鼠模型， 动物完全没有脂肪，但保持正常的体重。LD小鼠展示了许多 在患有肥胖诱导的OA的个体中观察到的临床体征（软骨下骨，全身 炎症、胰岛素抵抗、代谢紊乱和肌无力）。出乎意料的是，我们观察到， 保护LD膝关节免受OA。当将脂肪移植到LD小鼠中时，对OA的保护作用被逆转， 包括脂肪组织和脂肪组织分泌的脂肪因子，但不包括体重 - 是关节退化的关键介质。这些结果表明脂肪组织和介质 由脂肪组织分泌的细胞因子（脂肪因子）不利地影响软骨健康。 在该资助的指导K99部分，我们将使用小鼠产生生物工程设计的脂肪植入物， 诱导多能干细胞（iPSC）提供了一个平台，解构脂肪因子信号转导和研究 脂肪组织和关节健康的联系机制。这种方法，这是不可能的，以前没有 创造复杂而昂贵的转基因小鼠，解决了我们对肥胖理解的根本差距， 和OA。在独立的R 00部分，我们将利用再生医学的最新进展 开发和测试一种自我调节的细胞植入物，可以提供生物药物来对抗OA， 为柯林斯博士的独立研究生涯提供了平台，并为第一台R 01奠定了基础。的价值 平台的一个重要特点是可互换地提供广泛的潜在治疗方法的灵活性。利用这本小说， 灵活的平台，我们将劫持脂肪因子信号，以可调和良好的方式提供抗炎介质， 控制的方式作为一种新的再生治疗OA。由于iPSC平台可以很容易地容纳 编辑和改变各种细胞类型中的感兴趣的靶标，这种疗法的潜力是深远的， 许多慢性疾病（癌症、心血管疾病、糖尿病等）与病理性炎症有关 发信号。

PROJECT SUMMARY Osteoarthritis (OA) is the leading cause of pain and disability worldwide, and there are currently no disease modifying treatments available. While obesity-induced OA involves both metabolic and biomechanical factors, a key link is excess fat, or adipose tissue – a source of inflammatory mediators implicated in the pathogenesis of OA. The mechanistic influence of adiposity, biomechanical alterations, and metabolic syndrome have been difficult to determine and disentangle. To separate these factors, we used a mouse model of lipodystrophy (LD), in which the animals completely lack fat but maintain normal body mass. The LD mouse demonstrates many clinical signs observed in individuals with obesity-induced OA (sclerotic subchondral bone, systemic inflammation, insulin resistance, metabolic disturbance, and muscle weakness). Unexpectedly, we observed that LD knee joints are protected from OA. When fat was transplanted into LD mice protection from OA was reversed, implicating that adipose tissue, and factors secreted by adipose tissue called adipokines – but not body weight – are critical mediators of joint degeneration. These results suggest that adipose tissue and the mediators (adipokines) secreted by adipose tissue adversely affect cartilage health. In the mentored K99 portion of this grant, we will generate bioengineered designer adipose implants using murine induced pluripotent stem cells (iPSCs) to provide a platform to deconstruct adipokine signaling and investigate the mechanisms linking adipose tissue and joint health. This approach, which was not possible previously without creating complex and expensive transgenic mice, addresses a gap fundamental in our understanding of obesity and OA. In the independent R00 portion of this grant, we will leverage recent advances in regenerative medicine to develop and test a self-regulating cell-based implant that can provide biologic drugs to combat OA, laying the platform for Dr. Collins’ independent research career, and the groundwork for a first R01. The value of this platform is the flexibility to interchangeably deliver a wide range of potential therapeutics. Using this novel and flexible platform, we will hijack adipokine signaling to deliver anti-inflammatory mediators in a tunable and well- controlled manner as a novel regenerative therapy for OA. Since this iPSC platform could readily accommodate edits and alterations of targets of interest in a variety of cell types, the potential for this therapy is far-reaching, as many chronic diseases (cancer, cardiovascular disease, diabetes, etc.) have links to pathologic inflammatory signaling.