BCCMA: Cartilage Repair Strategies to Alleviate Arthritis Pain (Care AP): Targeting Pattern-Recognition to Reduce Pain-Related Pathology in Osteoarthritis

由于关节的影响，骨关节炎在美国军人和退伍军人中非常普遍 创伤和过度使用伤害。它的社会经济影响是巨大的，估计每年接近600亿美元， 而且目前还没有治疗疾病的方法。协作计划的总体目标是开发一种 治疗创伤后骨关节炎(PTOA)，将减轻疼痛和改善功能。我们假设 PTOA是由不良适应修复反应引起的，包括激活促炎通路 先天免疫，进而导致疼痛、功能丧失和结构衰退。本计划针对的是 通过两个高度整合的目标进行假说：(1)开发创新的非药理学和关节内 抑制局部疼痛和炎症的治疗，以及(2)优化基于间充质干细胞(MSC)的治疗 重建受损关节的治疗方法。 这项建议的目标是开发新的治疗方法，通过减少炎症来减轻与骨性关节炎相关的疼痛 以及通过抑制CD14受体而进行的骨重建。我们第一个发现了高水平的CD14 在骨关节炎患者中，和其他人随后将CD14与骨关节炎患者的疼痛联系起来。CD14是一种模式识别 单核细胞、巨噬细胞和破骨细胞(骨吸收髓系细胞)表达的受体， 增强对组织损伤的先天免疫反应，就像在PTOA中观察到的关节。我们的团队已经 现在证明，CD14的遗传缺陷可以减少小鼠关节损伤后的疼痛和骨重建， 并防止关节炎软骨损伤的进展。我们假设CD14受体激活 通过增强炎症和改变破骨细胞活性来促进骨性关节炎的疼痛和病理，以及 预期CD14阻断可以被开发为治疗疼痛和炎症的一种选择 在办公自动化中。我们将利用体外技术，疾病的小动物和大动物模型来了解这是如何 能有效抑制受体，减轻疼痛、炎症和关节病理。具体地说，在目标1中我们 将使用两种互补的PTOA小鼠模型来确定CD14的遗传缺陷是如何改变的 疼痛、炎症和骨骼重塑的模式，并改变破骨细胞的活动。我们将使用cell和 组织培养结合成像以确定关节组织中CD14的主要细胞来源。最后，在目标2中 我们将测试关节内抑制CD14是否可以减少疼痛的发展和PTOA的进展 在半月板损伤的小鼠和猪模型中。该项目将确立抗CD14治疗是安全的和 在PTOA的临床前模型中有效。作为临床检测的中和性抗CD14抗体的干扰 这一途径在人类中是可用的，这将为转化为未来的临床试验奠定基础 退伍军人和其他有骨性关节炎的人的治疗方法。

Osteoarthritis (OA) is highly prevalent in U.S. military service members and Veterans due to the impact of joint trauma and overuse injury. Its socioeconomic impact is substantial, estimated to approach $60 billion per year, and no disease-modifying treatments exist. The overall goal of the collaborative Program is to develop a treatment for post-traumatic osteoarthritis (PTOA) that will relieve pain and improve function. We hypothesize that PTOA is caused by maladaptive repair responses including activation of the pro-inflammatory pathways of innate immunity that in turn result in pain, loss of function and structural decline. This Program address the hypothesis through two highly-integrated aims: (1) developing innovative non-pharmacologic and intra-articular therapies inhibiting local pain and inflammation, and (2) optimizing mesenchymal stem cell (MSC)-based therapies for reconstruction of the damaged joint. The goal of this proposal is to develop novel therapy to diminish OA-associated pain by reducing inflammation and bone remodeling through inhibition of the receptor CD14. We were the first to discover high levels of CD14 in OA patients, and others subsequently linked CD14 to pain in OA patients. CD14 is a pattern-recognition receptor expressed by monocytes, macrophages and osteoclasts (bone-resorbing myeloid cells), that augments innate immune responses to tissue injury, like that observed in the joint in PTOA. Our group has now demonstrated that genetic deficiency of CD14 reduces pain and bone remodeling after joint injury in mice, and prevents progression of arthritic cartilage damage. We hypothesize that CD14 receptor activation promotes OA pain and pathology by enhancing inflammation and modifying osteoclast activity, and anticipate that CD14 blockade can be developed as a therapeutic option to treat pain and inflammation in OA. We will utilize in vitro techniques, small and large animal models of disease to understand how this receptor can be effectively inhibited to reduce pain, inflammation and joint pathology. Specifically, in Aim 1 we will use two complementary murine models of PTOA to determine how genetic deficiency of CD14 alters patterns of pain, inflammation, and bone remodeling, and modifies osteoclast activity. We will use cell and tissue culture along with imaging to identify the main cellular sources of CD14 in joint tissues. Finally, in Aim 2 we will test whether intra-articular inhibition of CD14 can reduce development of pain and progression of PTOA in murine and porcine models of meniscal injury. This project will establish anti-CD14 therapy as safe and effective in preclinical models of PTOA. As clinically-tested neutralizing anti-CD14 antibodies to interfere with this pathway in humans are available, this will set the stage for translation to future clinical trials of this approach in Veterans and others with OA.