Intrinsic Repair of the Knee Meniscus

膝关节半月板的内在修复

• 批准号: 7673867
• 负责人: Farshid Guilak
• 金额: $ 29.33万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-09-01 至 2012-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7673867
• 关键词: Acute; Anabolism; Anti-Inflammatory Agents; Anti-inflammatory; Antibodies; Arthritis; Biochemical; Biological Models; Biology; Biomechanics; Biomedical Engineering; Cells; Chimeric Proteins; Chronic; Collagen; Dependence; Dinoprostone; Elastin; Environment; Exhibits; Exposure to; Genetic Transcription; Goals; Growth Factor; Healed; Health; In Vitro; Inflammation; Inflammation Mediators; Inflammatory; Injury; Interleukin-1; Interleukin-17; Interleukins; Interstitial Collagenase; Joints; Knee; Knee joint; Lead; Matrix Metalloproteinases; Mechanical Stress; Mechanics; Mediating; Mediator of activation protein; Meniscus structure of joint; Messenger RNA; Metabolic; Metabolism; Modality; Modeling; Nitric Oxide; Osteoarthrosis Deformans; Pain; Pathway interactions; Pharmaceutical Preparations; Physiological; Process; Production; Property; Protein Biosynthesis; Proteoglycan; Recording of previous events; Relative (related person); Research Personnel; Rheumatology; Role; Site; Speed; Stress; Structure; Temperature; Tissues; Tumor Necrosis Factor-alpha; Up-Regulation; Work; anakinra; articular cartilage; base; common treatment; cytokine; disability; disorder prevention; healing; improved; in vitro Model; inhibitor/antagonist; insight; mRNA Expression; multidisciplinary; novel; polypeptide; receptor; repaired; response; tibia; transmission process

DESCRIPTION (provided by applicant): The menisci are intra-articular fibrocartilaginous structures essential to the normal function of the knee joint. Damage or loss of the menisci often results in progressive osteoarthritic degeneration of the articular cartilage and other joint tissues, leading to significant pain and disability. While the biomechanical contributions of the meniscus to the health of the knee joint are well understood, the biochemical influence of the menisci on joint inflammation is not known. Our prior work has demonstrated that mechanical stress alters the metabolism of menisci, inducing production of nitric oxide (NO) and prostaglandin E2 (PGE2) production. NO and PGE2 production is stimulated by certain cytokines and growth factors, and NO and PGE2 (depending on the rates and sites of production) can serve as pro- or anti-inflammatory molecules. The goal of this study is to determine the influence of these mediators on collagen matrix biosynthesis in the meniscus. We hypothesize that dynamic mechanical stress modifies meniscus collagen mRNA transcription and protein synthesis through pathways that involve NO and PGE2. Furthermore, we hypothesize that certain cytokines act in an additive or synergistic manner with mechanical stress to induce meniscal NO and PGE2 production. We will pursue the following Specific Aims: (1) determine the effects of static and dynamic compression on collagen mRNA expression and protein synthesis in explants of meniscus; (2) determine the role of mechanically-induced NO and PGE2 in regulating collagen synthesis; (3) determine the interaction of mechanical stress with interleukin 1, interleukin 17, and tumor necrosis factor alpha in the production of pro-inflammatory mediators, and (4) determine the interaction between the NO and PGE2 pathways in these regulatory processes. This five-year project brings together a multidisciplinary team with expertise in bioengineering, biology, and rheumatology to study the role of biomechanical factors in mediating inflammation of the meniscus. The long-term goal of these studies is to better understand the mechanisms through which altered mechanical loading of the meniscus influences pain, inflammation, and degeneration of the knee joint. Identification of these mechanisms will hopefully lead to new treatments that exploit optimal mechanical and biochemical modalities for the prevention of disease.

描述（由申请人提供）：半月板是膝关节正常功能必不可少的关节内纤维纤维结构。半月板的损伤或损失通常会导致关节软骨和其他关节组织的进行性骨关节炎变性，从而导致严重的疼痛和残疾。虽然弯弯甲对膝关节健康的生物力学贡献已得到充分了解，但半月板对关节炎症的生化影响尚不清楚。我们先前的工作表明，机械应力改变了半月板的代谢，诱导一氧化氮（NO）和前列腺素E2（PGE2）产生的产生。某些细胞因子和生长因子刺激了NO和PGE2的产生，并且NO和PGE2（取决于生产的速率和位点）可以用作促或抗炎分子。这项研究的目的是确定这些介体对半月板中胶原蛋白基质生物合成的影响。我们假设动态机械应力通过涉及NO和PGE2的途径修饰了半月板胶原mRNA转录和蛋白质合成。此外，我们假设某些细胞因子以机械应力的加性或协同方式起作用，以诱导半月板NO和PGE2产生。我们将追求以下特定目的：（1）确定静态和动态压缩对弯曲层植物中胶原mRNA表达和蛋白质合成的影响； （2）确定机械诱导的NO和PGE2在调节胶原蛋白合成中的作用； （3）确定机械应力与白介素1，白介素17和肿瘤坏死因子α在促炎性介体的产生中的相互作用，（4）（4）在这些调节过程中确定NO和PGE2途径之间的相互作用。这个五年的项目汇集了一个具有生物工程，生物学和风湿病学专业知识的跨学科团队，以研究生物力学因素在介导拟象中的炎症中的作用。这些研究的长期目标是更好地了解弯月面的机械负荷会影响疼痛，炎症和膝关节变性的机制。鉴定这些机制将有望导致新的治疗方法，从而利用最佳的机械和生化方式来预防疾病。