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

BCCMA：缓解关节炎疼痛的软骨修复策略（Care AP）：以模式识别为目标，减少骨关节炎中与疼痛相关的病理

• 批准号: 10620628
• 负责人: Carla Rose Scanzello
• 金额: --
• 依托单位: PHILADELPHIA VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-04-01 至 2027-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10620628
• 关键词: Ablation; Acceleration; Acute; Address; Animal Disease Models; Animals; Anti-Inflammatory Agents; Antibodies; Arthralgia; Arthritis; Behavior; Bone Resorption; Bone remodeling; CD14 Antigen; CD14 gene; Caring; Cartilage; Cell Culture Techniques; Chronic; Clinical; Clinical Trials; Cumulative Trauma Disorders; Data; Degenerative polyarthritis; Development; Disease; Dose; Drug Delivery Systems; Ensure; Future; General Population; Genetic; Goals; Human; Image; In Vitro; Incidence; Individual; Inflammation; Inflammatory; Injury; Innate Immune Response; Joints; Link; Macrophage; Measures; Medial meniscus structure; Mediating; Medical; Mesenchymal Stem Cells; Methods; Military Personnel; Miniature Swine; Modeling; Molecular; Mus; Mutant Strains Mice; Myeloid Cells; Natural Immunity; Neutralization Tests; Operative Surgical Procedures; Osteitis; Osteoclasts; Pain; Pathology; Pathway interactions; Patient Selection; Patients; Pattern; Pattern Recognition; Pattern recognition receptor; Pharmaceutical Preparations; Phase; Positioning Attribute; Pre-Clinical Model; Quality of life; Reagent; Receptor Activation; Receptor Inhibition; Receptor Signaling; Rehabilitation therapy; Replacement Arthroplasty; Reproducibility; Research Personnel; Source; Surgical Models; Synovitis; Techniques; Testing; Therapeutic; Tissues; Toll-like receptors; Translations; Traumatic Arthropathy; Veterans; Work; active duty; arthritic pain; cartilage repair; chronic pain; clinical care; economic impact; functional improvement; improved; innovation; insight; joint function; joint injury; loss of function; meniscus injury; military service; monocyte; mouse model; novel; novel strategies; novel therapeutics; osteoarthritis pain; osteoclastogenesis; pain behavior; pain inhibition; pain reduction; pain relief; pharmacologic; phase change; pilot test; porcine model; prevent; programs; receptor; reconstruction; repair strategy; repaired; response; service member; socioeconomics; spontaneous pain; stem cell therapy; subchondral bone; tissue culture; tissue injury; tool; translational approach

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.

骨关节炎（OA）在美国军人和退伍军人中非常普遍，这是由于关节炎的影响。 创伤和过度使用损伤。其社会经济影响巨大，估计每年接近600亿美元， 并且不存在改善疾病的治疗方法。合作计划的总体目标是制定一个 治疗创伤后骨关节炎（PTOA），将缓解疼痛和改善功能。我们假设 PTOA是由适应不良的修复反应引起的，包括炎症反应的促炎途径的激活。 先天性免疫力反过来导致疼痛、功能丧失和结构衰退。该计划旨在解决 假设通过两个高度整合的目标：（1）开发创新的非药物和关节内 抑制局部疼痛和炎症的疗法，以及（2）优化基于间充质干细胞（MSC）的疗法 修复受损关节的治疗方法。 该提案的目标是开发新的治疗方法，通过减少炎症来减少OA相关疼痛 和通过抑制受体CD14的骨重建。我们是第一个发现高水平的CD14 在OA患者中，其他人随后将CD14与OA患者的疼痛联系起来。CD14是一种模式识别 由单核细胞、巨噬细胞和破骨细胞（骨吸收骨髓细胞）表达的受体， 增强对组织损伤的先天免疫反应，如在PTOA中的关节中观察到的。我们集团 现在证明，CD14的遗传缺陷减少了小鼠关节损伤后的疼痛和骨重塑， 并防止关节炎软骨损伤的进展。我们假设CD14受体活化 通过增强炎症和改变破骨细胞活性促进OA疼痛和病理学， 预期CD14阻断剂可被开发为治疗疼痛和炎症的治疗选择 在OA。我们将利用体外技术，小型和大型动物疾病模型，以了解这是如何 受体可有效抑制，以减轻疼痛、炎症和关节病理。具体而言，在目标1中， 将使用两种互补的PTOA小鼠模型来确定CD14的遗传缺陷如何改变 疼痛，炎症和骨重建的模式，并改变破骨细胞活性。我们将使用细胞和 组织培养沿着成像以鉴定关节组织中CD 14的主要细胞来源。在Aim 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 在小鼠和猪的尿道损伤模型中。该项目将确定抗CD14治疗是安全的， 在PTOA的临床前模型中有效。作为临床测试的中和抗CD14抗体， 这一途径在人类中是可用的，这将为将来的临床试验奠定基础。 在退伍军人和其他OA患者中的方法。