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 会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 估计每年花费接近 600 亿美元，并且不存在缓解疾病的治疗方法。当前的 据了解，PTOA 是由适应不良修复反应引起的，包括亲 先天免疫的炎症途径，进而导致疼痛、功能丧失和结构衰退。这 该项目提出了这样的假设：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。存在于关节中的天然间充质干细胞 (MSC) 是操纵分化成软骨细胞的重要靶点。这些联合驻地 MSC 包括 软骨祖细胞、滑液、滑膜和脂肪组织中的间充质干细胞。 SOX9（SRY型高迁移率 group box 基因-9) 是 MSC 软骨形成的主要转录因子。我们生产了一个 带超正电荷的 SOX9 (scSOX9) 可以渗入 MSC 并诱导软骨形成。我们 在急性软骨损伤模型中证明，scSOX9 通过以下方式诱导透明样软骨修复： 促进骨髓间充质干细胞（BM-MSCs）的软骨形成。通过使用内侧半月板横断术 (MMT) 诱导的大鼠 PTOA 模型，我们将通过利用软骨形成来测试 scSOX9 的治疗效果 这些关节驻留的 MSC 具有再生透明软骨的潜力。疼痛和关节功能将 通过测量疾病不同时间点的行为变化来对活体动物进行临床评估 课程。软骨再生或修复以及滑膜炎的程度将通过先进的成像进行量化 系统。实验结束时，修复软骨的生物力学特性将为 使用生物动量压痕技术对带有软骨下骨的完整软骨进行测量。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和 免疫组织化学。