Targeting Molecular Transducers of Exercise for Osteoarthritis Therapies

骨关节炎(OA)对退伍军人的影响不成比例，导致更多的疼痛和功能限制 与普通人群相比。目前还没有针对骨性关节炎和当前疼痛的疾病修正治疗方法 药物(如阿片类药物和非类固醇抗炎药)的长期疗效和副作用有限。未解决 细胞和分子关节炎症被认为是骨关节炎进展的中心机制。然而， 在这一领域取得进展的一个障碍是确定慢性骨性关节炎炎症的原因以及如何解决它们。 申请者克服这一障碍的长期目标是了解如何 运动疗法可以减少骨性关节炎的炎症和疼痛，从而可以识别协同作用的药物靶点 为治疗用途而开发的。这种应用的前提是巨噬细胞依赖于脂类代谢。 重新编程以完成抗炎替代激活。这里的目标是确定如何 关节内脂肪组织脂解通过调节抗炎巨噬细胞改善关节炎症 极化。中心假设是关节炎症的消退需要时间上的偶联。 髌下脂肪垫(IFP)脂肪分解与巨噬细胞脂质摄取和脂肪酸代谢驱动替代 激活。这一假设是基于申请人令人兴奋的初步数据显示的 运动触发膝关节滑膜一过性促炎细胞因子和巨噬细胞的产生 和IFP，在运行的第14天完全解决。值得注意的是，炎症的诱导和消退发生在 伴随着IFP脂解、纤维化和脂肪生成的短暂周期。建议的理由是 研究是对关节组织代谢物和细胞之间因果关系的理解 炎症介质有可能通过促进基本的治疗而创造新的治疗机会 关于关节炎症是如何调节的知识。拥有强大的初步数据和小规模 动物运动、新陈代谢和OA研究，申请者将通过进行三个具体的研究来检验假设 目的：1)确定关节内脂肪组织脂肪分解如何介导巨噬细胞活化，关节 炎症和创伤后骨性关节炎；2)确定巨噬细胞脂质摄取和脂肪酸的作用 氧化对关节炎症和创伤后骨性关节炎的发展；以及3)发展成联合的 以脂代谢为靶点的物理和生物干预策略减少关节炎症和疼痛 慢性膝关节骨性关节炎的临床前模型。AIMS 1和AIMS 2将在解析和非解析的小鼠模型中测试 通过车轮运行和内侧半月板(DMM)模型的失稳来解决关节炎症， 分别进行了分析。这些模型已经在申请人手中建立为可行的，将用于测试 确定关节内脂质对关节炎症具有促进或抗消解作用的原因机制。 在目标1中，这些包括一种可诱导的遗传方法来阻止关节中的脂肪分解或药物 增强脂肪分解的方法。在第二个目标中，将使用可诱导遗传方法来抑制 过氧化物酶体增殖物激活的巨噬细胞受体γ(PPARγ)或从药理上刺激PPARγ。 第三个目标是在dmm模型中结合物理和PPARγ药物治疗，以测试 协同作用，比单独锻炼更能改善疼痛和功能。通过专注于蜂窝网络 和分子换能器，这项拟议的研究测试了新的、创新的范式 设计药物以加强骨性关节炎运动疗法的疗效。拟议的研究是 具有重要意义，因为它将启动滑膜关节代谢如何被操纵的系统研究 促进关节炎症消退。这些知识对其他办公自动化来说也是很重要的 治疗，如优化关节环境以支持干细胞和组织工程学 再生医学战略。

Osteoarthritis (OA) disproportionately affects veterans, resulting in more pain and functional limitations compared to the general population. No disease-modifying treatments exist for OA, and current pain medications (e.g., opioids and NSAIDs) have limited long-term efficacy and adverse side effects. Unresolved cellular and molecular joint inflammation is recognized as the central mechanism of OA progression. However, a barrier to progress in the field is identifying the causes of chronic OA inflammation and how to resolve them. The applicant's long-term goal for overcoming this barrier is to understand the molecular mechanisms of how exercise therapy reduces OA inflammation and pain so that synergistic drug targets can be identified and developed for therapeutic use. The premise of this application is that macrophages depend on lipid metabolism reprogramming to complete anti-inflammatory alternative activation. The objective here is to determine how intra-articular adipose tissue lipolysis modifies joint inflammation by regulating anti-inflammatory macrophage polarization. The central hypothesis is that the resolution of joint inflammation requires the temporal coupling of infra-patellar fat pad (IFP) lipolysis with macrophage lipid uptake and fatty acid metabolism to drive alternative activation. This hypothesis has been developed based on the applicant's exciting preliminary data showing that exercise triggers a transient induction of pro-inflammatory cytokines and macrophages in the knee synovium and IFP, which fully resolves by day 14 of running. Notably, the induction and resolution of inflammation occurs in parallel with a transient cycle of IFP lipolysis, fibrosis, and lipogenesis. The rationale for the proposed research is that an understanding of the causal relationship between joint tissue metabolites and cellular inflammatory mediators has the potential to generate new therapeutic opportunities by advancing fundamental knowledge about how joint inflammation is regulated. With strong preliminary data and expertise in small animal exercise, metabolism, and OA studies, the applicant will test the hypothesis by pursuing three specific aims: 1) Determine how intra-articular adipose tissue lipolysis mediates macrophage activation, joint inflammation, and post-traumatic OA; 2) Determine the effect of macrophage lipid uptake and fatty acid oxidation on joint inflammation and the development of post-traumatic OA; and 3) Develop a combined physical and biologic intervention strategy targeting lipid metabolism to reduce joint inflammation and pain in a pre-clinical model of chronic knee OA. Aims 1 and 2 will be tested in mouse models of resolving and non- resolving joint inflammation using wheel running and destabilization of the medial meniscus (DMM) models, respectively. The models, which have been established as feasible in the applicant's hands, will be used to test causal mechanisms that establish the pro- or anti-resolving effects of intra-articular lipids on joint inflammation. In aim 1, these include an inducible genetic approach to block lipolysis in the joint or a pharmacologic approach to enhance lipolysis. In the second aim, an inducible genetic approach will be used to inhibit peroxisome proliferator activated receptor-γ (PPARγ) in macrophages or stimulate PPARγ pharmacologically. The third aim combines physical and PPARγ pharmacologic treatments in the DMM model to test for synergistic interactions that improve pain and function more than exercise alone. By focusing on the cellular and molecular transducers of OA exercise therapy, the proposed research tests new, innovative paradigms for designing drugs to potentiate the therapeutic effects of OA exercise therapy. The proposed research is significant because it will initiate the systematic study of how synovial joint metabolism may be manipulated to promote the resolution of joint inflammation. This knowledge is also expected to be important for other OA therapies, such as optimizing the joint environment to support stem cell and tissue-engineering-based regenerative medicine strategies.