Biomechanical Regulation of Intra-Articular Adipose Tissue Inflammation

关节内脂肪组织炎症的生物力学调节

• 批准号: 8773923
• 负责人: TIMOTHY M GRIFFIN
• 金额: $ 8.55万
• 依托单位: OKLAHOMA MEDICAL RESEARCH FOUNDATION
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-01 至 2017-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8773923
• 关键词: Abdomen; Adipocytes; Adipose tissue; Advanced Development; Anti-Inflammatory Agents; Anti-inflammatory; Arthritis; Attenuated; Biocompatible Materials; Biomechanics; Cytoskeleton; Data; Degenerative polyarthritis; Deposition; Development; Dichloromethylene Diphosphonate; Disease; Endocrine; Exercise; Extracellular Matrix; Fatty acid glycerol esters; Fibronectins; Fibrosis; Functional disorder; Gene Expression; Gene Proteins; Glycoproteins; Goals; Growth Factor; Harvest; Health; Human; Hypertrophy; Infiltration; Inflammation; Inflammation Mediators; Inflammatory; Joint Capsule; Joints; Knee; Knee joint; Knowledge; Laboratories; Lead; Liposomes; Mechanical Stimulation; Mediating; Mediator of activation protein; Metabolic; Modeling; Molecular; Mus; Musculoskeletal; Musculoskeletal Diseases; Musculoskeletal System; Obesity; Operative Surgical Procedures; Organ; Outcome Measure; Paracrine Communication; Pathology; Patients; Physiological; Prevention; Production; Property; Public Health; Rattus; Regulation; Replacement Arthroplasty; Research; Resolution; Review Literature; Role; Running; Sampling; Signal Transduction; Site; Skeleton; Skin; System; Testing; Time; Tissues; Work; adipocyte differentiation; adipokines; arthropathies; base; biological adaptation to stress; cytokine; disability; improved; in vivo; inhibitor/antagonist; joint function; joint injury; joint loading; macrophage; mouse model; new therapeutic target; novel; paracrine; prevent; protein expression; research clinical testing; research study; response; subcutaneous; therapy development; Abdomen; Adipocytes; Adipose tissue; Advanced Development; Anti-Inflammatory Agents; Anti-inflammatory; Arthritis; Attenuated; Biocompatible Materials; Biomechanics; Cytoskeleton; Data; Degenerative polyarthritis; Deposition; Development; Dichloromethylene Diphosphonate; Disease; Endocrine; Exercise; Extracellular Matrix; Fatty acid glycerol esters; Fibronectins; Fibrosis; Functional disorder; Gene Expression; Gene Proteins; Glycoproteins; Goals; Growth Factor; Harvest; Health; Human; Hypertrophy; Infiltration; Inflammation; Inflammation Mediators; Inflammatory; Joint Capsule; Joints; Knee; Knee joint; Knowledge; Laboratories; Lead; Liposomes; Mechanical Stimulation; Mediating; Mediator of activation protein; Metabolic; Modeling; Molecular; Mus; Musculoskeletal; Musculoskeletal Diseases; Musculoskeletal System; Obesity; Operative Surgical Procedures; Organ; Outcome Measure; Paracrine Communication; Pathology; Patients; Physiological; Prevention; Production; Property; Public Health; Rattus; Regulation; Replacement Arthroplasty; Research; Resolution; Review Literature; Role; Running; Sampling; Signal Transduction; Site; Skeleton; Skin; System; Testing; Time; Tissues; Work; adipocyte differentiation; adipokines; arthropathies; base; biological adaptation to stress; cytokine; disability; improved; in vivo; inhibitor/antagonist; joint function; joint injury; joint loading; macrophage; mouse model; new therapeutic target; novel; paracrine; prevent; protein expression; research clinical testing; research study; response; subcutaneous; therapy development

DESCRIPTION (provided by applicant): Intra-articular adipose tissue is an important structural tissue within joints and is increasingly recognized as a critical mediator of inflammation. The extrinsic factors that regulate intra-articular adipose tissue inflammation are unknown. Identifying such factors and the molecular mechanisms by which they impact joint inflammation will advance the development of new treatments for joint injury and musculoskeletal disability. The applicant's long-term goal is to develop therapies to treat and prevent obesity-associated osteoarthritis by identifying biomechanical and metabolic factors that promote the resolution of joint inflammation. This application focuses on the mechanobiology of inflammatory signaling in intra-articular fat pads. The objective here is to identify the effect of joint loading on the expression of inflammatory adipokines within the infrapatellar fat pad (IFP) and to determine whether adipose tissue macrophages (ATMs) mediate this response. The central hypothesis is that physiologic joint loading due to exercise induces resident ATMs to initiate a pro-fibrotic response that restricts adipocyte hypertrophy and thereby attenuates pro-inflammatory adipokine expression. The hypothesis and focus on ATMs as mechano-sensitive pro-fibrotic mediators in the IFP is based on a comprehensive literature review and preliminary data generated in the applicant's laboratory. These findings indicate that compared to subcutaneous fat, the IFP has an elevated expression of pro-fibrotic growth factors, fibronectin, and cytokines. Preliminary wheel running studies also show that the IFP is a dynamic structural tissue that increases extracellular matrix deposition in response to exercise. Guided by these data, the project will test the hypothesis using two specific aims: 1) Determine the time-course of in vivo and ex vivo biomechanical stimulation on mediators of macrophage infiltration, polarization, and IFP fibrosis; and 2) Determine the requirement of resident ATMs on biomechanically-stimulated IFP fibrosis and adipokine expression. A well- established voluntary wheel running mouse model will be used to evaluate the effect of increased IFP mechanical stimulation on gene, protein, and cellular outcome measures. The applicant's lab will also utilize an ex vivo tissue compression system for conducting compressive loading experiments on rat IFP samples. Under the second aim, resident ATMs will be depleted in these in vivo and ex vivo models with liposomal clodronate to determine if ATMs mediate the effect of biomechanical stimulation on IFP fibrosis and adipokine expression. The proposed research is significant because it is expected that biomechanical stimulation will greatly contribute to the paracrine inflammatory signaling function of intra-articular fat pads. Ultimately, such knowledge is expected to lead to the development of novel therapeutic targets for pre-clinical testing in the prevention or treatment of diseases involving musculoskeletal inflammation and physical disability.

描述（由申请人提供）：关节内脂肪组织是关节内的重要结构组织，越来越多地被认为是炎症的关键介体。调节关节内脂肪组织炎症的外部因素尚不清楚。确定影响关节炎症的这些因素以及分子机制将推动针对关节损伤和肌肉骨骼障碍的新疗法的发展。申请人的长期目标是开发治疗和预防与肥胖相关的骨关节炎，通过鉴定促进关节炎症解决的生物力学和代谢因素，以治疗和预防肥胖相关的骨关节炎。该应用的重点是关节内脂肪垫中炎症信号传导的机械生物学。此处的目的是确定关节负荷对炎症性脂肪垫（IFP）内炎症性脂肪因子表达的影响，并确定脂肪组织巨噬细胞（ATM）是否介导了这种反应。中心假设是，由于运动而引起的生理关节负荷会诱导居民自动取款机发起促纤维化反应，从而限制脂肪细胞肥大，从而减轻促炎性脂肪因子的表达。假设和关注ATM作为IFP中的机械敏感性纤维化介体的基于申请人实验室中产生的全面文献综述和初步数据。这些发现表明，与皮下脂肪相比，IFP的促纤维化生长因子，纤连蛋白和细胞因子的表达升高。 初步的车轮运行研究还表明，IFP是一种动态结构组织，可响应运动而增加细胞外基质沉积。在这些数据的指导下，该项目将使用两个特定目的检验假设：1）确定体内和离体生物力学刺激的时间顺序，这些刺激对巨噬细胞浸润，极化和IFP纤维化的介体刺激； 2）确定居民ATM对生物力学刺激的IFP纤维化和脂肪因子表达的需求。良好的自愿车轮运行小鼠模型将用于评估IFP机械刺激对基因，蛋白质和细胞结局测量指标增加的影响。申请人的实验室还将利用离体组织压缩系统对大鼠IFP样品进行压缩载荷实验。在第二个目标下，将在具有脂质体氯膦酸盐的体内和离体模型中耗尽居民ATM，以确定ATM是否介导生物力学刺激对IFP纤维化和脂肪因子表达的影响。拟议的研究很重要，因为预计生物力学刺激将极大地有助于关节内脂肪垫的旁分泌炎症信号传导功能。最终，这种知识有望导致在预防或治疗涉及肌肉骨骼炎症和身体残疾的疾病中进行临床前测试的新型治疗靶标。