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: 10514590
• 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/10514590
• 关键词: Acute; Address; Adipose tissue; Animals; Anti-Inflammatory Agents; Antibodies; Arthralgia; Biological Assay; Biomechanics; CD14 gene; Cartilage; Cartilage injury; Charge; Chondrocytes; Chondrogenesis; Clinical; Collagen Type II; Cumulative Trauma Disorders; Degenerative polyarthritis; Disease; Fibrocartilages; Genes; Goals; Green Fluorescent Proteins; Hematopoietic Stem Cell Mobilization; Histopathology; Human; Hyaline Cartilage; Hybrids; Immunohistochemistry; In Situ; In Vitro; Inflammation; Inflammatory; Intervention; Intra-Articular Injections; Joints; Knee joint; Liposomes; Macrophage; Measures; Medial meniscus structure; Mesenchymal Stem Cells; Methods; Military Personnel; Modeling; Natural Immunity; Natural regeneration; Pain; Pathogenesis; Pathway interactions; Penetration; Pharmacological Treatment; Play; Polymers; Procedures; Property; Rattus; Role; Site; Standardization; Surface; Synovial Fluid; Synovial Membrane; Synovitis; System; TLR4 gene; Technology; Testing; Therapeutic Effect; Therapeutic procedure; Time; Traumatic Arthropathy; Treatment Protocols; Veterans; articular cartilage; behavior change; bone marrow mesenchymal stem cell; cartilage degradation; cartilage regeneration; cartilage repair; cellular targeting; chondrogenesis factor; clinical development; economic impact; experimental study; functional improvement; imaging system; improved; in vivo; joint function; joint injury; loss of function; military service; military veteran; monocyte; negative affect; novel therapeutics; pain relief; particle; 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