Stimulation of Native Joint-resident Precursors for Cartilage Repair in Osteoarthritis

刺激天然关节前体促进骨关节炎软骨修复

• 批准号: 10015959
• 负责人: CONG-QIU CHU
• 金额: --
• 依托单位: PORTLAND VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-10-01 至 2024-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10015959
• 关键词: Acute; Address; Adipose tissue; Animals; Anti-Inflammatory Agents; Antibodies; Arthralgia; Biological Assay; Biomechanics; Bone Marrow; CD14 gene; Cartilage; Cartilage injury; Charge; Chondrocytes; Chondrogenesis; Clinical; Collagen Type II; Cumulative Trauma Disorders; Degenerative polyarthritis; Disease; Fibrocartilages; Genes; Goals; Green Fluorescent Proteins; Histopathology; Human; Hyaline Cartilage; Hybrids; Immunohistochemistry; In Situ; In Vitro; Inflammation; Inflammatory; Intervention; Intra-Articular Injections; Joints; Knee joint; Liposomes; Measures; Medial meniscus structure; Mesenchymal Stem Cells; Methods; Military Personnel; Modeling; Natural Immunity; Natural regeneration; Pain; Pathogenesis; Pathway interactions; Pharmacological Treatment; Play; Polymers; Procedures; Property; Rattus; Role; Site; Standardization; Structure; Surface; Synovial Fluid; Synovial Membrane; Synovitis; System; TLR4 gene; Technology; Testing; Therapeutic Effect; Therapeutic procedure; Time; Treatment Protocols; Veterans; articular cartilage; base; behavior change; cartilage degradation; cartilage regeneration; cartilage repair; cellular targeting; chondrogenesis factor; clinical development; experimental study; imaging system; improved; improved functioning; in vivo; joint function; joint injury; loss of function; macrophage; military service; military veteran; monocyte; negative affect; novel therapeutics; pain relief; precursor cell; protective effect; repaired; response; service member; socioeconomics; stem cell self renewal; stem cells; subchondral bone; synergism; targeted delivery; therapeutic evaluation; transcription factor

Osteoarthritis (OA), in particular, post-traumatic osteoarthritis (PTOA) 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. Current understanding is 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 project addresses the hypothesis that promotion of hyaline cartilage repair will effectively alter the course of PTOA, relieve joint pain and improve joint function. Native mesenchymal stem cells (MSC) residing in the joint are important targets for manipulation to differentiate into chondrocytes. These joint-resident MSCs include cartilage progenitor cells, MSCs in synovial fluid, synovium and adipose tissue. SOX9 (SRY-type high-mobility group box gene-9) is the master transcription factor for chondrogenesis of MSCs. We have produced a superpositively charged SOX9 (scSOX9) which can penetrate into MSCs and induce chondrogenesis. We have demonstrated in an acute cartilage injury model that scSOX9 induced hyaline-like cartilage repair by promoting chondrogenesis of bone marrow derived MSCs (BM-MSCs). By using medial meniscal transection (MMT) induced rat PTOA model, we will test the therapeutic effect of scSOX9 by harnessing the chondrogenic potential of these joint-resident MSCs for regeneration of hyaline cartilage. Pain and joint function will be assessed clinically in live animals by measuring behavior changes at different time points of the disease course. The degree of cartilage regeneration or repair and synovitis will be quantified by advanced imaging system. At the termination of experiments, the biomechanical property of the repaired cartilage will be measured on intact cartilage with subchondral bone using biomomentum indentation technology. Cartilage degradation, repair and synovitis will also be determined by standardized methods of histopathology and immunohistochemistry.

骨关节炎（OA），特别是创伤后骨关节炎（PTOA）在美国军队中非常普遍 成员和退伍军人由于关节创伤和过度使用损伤的影响。其社会经济影响是 估计每年接近600亿美元，并且不存在改变疾病的治疗方法。电流 PTOA是由适应不良的修复反应引起的，包括激活前 先天免疫的炎症途径，这反过来又导致疼痛，功能丧失和结构衰退。这 该项目解决了促进透明软骨修复将有效改变 PTOA，缓解关节疼痛，改善关节功能。天然间充质干细胞（MSC）驻留在关节中 是分化成软骨细胞的重要操作目标。这些联合驻留MSC包括 软骨祖细胞、滑液、滑膜和脂肪组织中的MSC。SOX 9（SRY型高迁移率 组盒基因-9）是MSC软骨形成的主要转录因子。我们制作了一个 在一些实施方案中，细胞可以具有带超电荷的SOX 9（scSOX 9），其可以渗透到MSC中并诱导软骨形成。我们 已经在急性软骨损伤模型中证明，scSOX 9通过以下方式诱导透明样软骨修复： 促进骨髓来源的MSC（BM-MSC）的软骨形成。通过内侧半月板横断 (MMT)诱导的大鼠PTOA模型，我们将通过利用软骨形成因子来测试scSOX 9的治疗效果。 这些关节驻留MSC的透明软骨再生的潜力。疼痛和关节功能将 通过测量疾病不同时间点的行为变化在活体动物中进行临床评估 当然了软骨再生或修复以及滑膜炎的程度将通过先进的成像技术进行量化 系统在实验结束时，修复软骨的生物力学性能将是 使用生物动量压痕技术在具有软骨下骨的完整软骨上测量。软骨 降解、修复和滑膜炎也将通过组织病理学的标准化方法来确定， 免疫组化