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.

由于关节的影响，骨关节炎 (OA) 在美国军人和退伍军人中非常普遍。 外伤和过度使用损伤。其社会经济影响巨大，估计每年接近 600 亿美元， 并且不存在缓解疾病的治疗方法。该合作计划的总体目标是开发一个 治疗创伤后骨关节炎 (PTOA)，可缓解疼痛并改善功能。我们假设 PTOA 是由适应不良修复反应引起的，包括促炎途径的激活 先天免疫反过来会导致疼痛、功能丧失和结构衰退。该计划解决了 通过两个高度整合的目标提出假设：（1）开发创新的非药物和关节内治疗 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 重建受损关节的疗法。 该提案的目标是开发新疗法，通过减少炎症来减轻 OA 相关疼痛 以及通过抑制受体 CD14 进行骨重塑。我们是第一个发现高水平 CD14 的人 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，就像在 PTOA 关节中观察到的那样。我们组有 现在证明 CD14 的遗传缺陷可以减轻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 OA 疼痛和病理，以及 预计 CD14 阻断可以开发为治疗疼痛和炎症的治疗选择 在办公自动化中。我们将利用体外技术、小型和大型动物疾病模型来了解这一现象是如何发生的。 受体可被有效抑制，从而减轻疼痛、炎症和关节病理。具体来说，在目标 1 中，我们 将使用两种互补的 PTOA 小鼠模型来确定 CD14 遗传缺陷如何改变 疼痛、炎症和骨重塑的模式，并改变破骨细胞的活性。我们将使用细胞和 组织培养结合成像来识别关节组织中 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生和 PTOA 的进展 在小鼠和猪的半月板损伤模型中。该项目将建立安全、可靠的抗 CD14 疗法 在 PTOA 临床前模型中有效。作为临床测试的中和抗 CD14 抗体，可干扰 该途径在人类中是可用的，这将为将该途径转化为未来的临床试验奠定基础 退伍军人和其他患有 OA 的人的方法。