Mechanisms of Articular Cartilage Lubrication

关节软骨润滑的机制

• 批准号: 7590096
• 负责人: Robert L Sah
• 金额: $ 15.45万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-05-10 至 2011-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7590096
• 关键词: Address; Biomedical Engineering; Bioreactors; Cartilage; Collaborations; Condition; Conditioned Culture Media; Degenerative polyarthritis; Disease; Enzymes; Fibroblasts; Friction; Goals; Health; Human; Hyaluronan; Immune; Immunology; In Vitro; Injury; Interdisciplinary Study; Interleukin-12; Joints; Knowledge; Liquid substance; Localized; Lubricants; Lubrication; MAPK14 gene; Messenger RNA; Molecular; Molecular Weight; Motion; Pathway interactions; Postdoctoral Fellow; Proteins; Radiolabeled; Regulation; Relative (related person); Research; Research Personnel; Rheumatoid Arthritis; Scientist; Signal Pathway; Small Interfering RNA; Solutions; Supervision; Surface; Synovial Fluid; Testing; Time; Tissue Engineering; Tissues; United States National Institutes of Health; Vesicle; Weight-Bearing state; Work; articular cartilage; base; cytokine; hyaluronan synthase 1; in vivo; inhibitor/antagonist; injured; parent grant; radiotracer; small molecule; trafficking

DESCRIPTION (provided by applicant): Bioengineering Joint Lubricants from Cultured Synoviocytes This proposed revision seeks to augment the parent grant, NIH R01 AR051565 Mechanisms of Articular Cartilage Lubrication, by Building an Interdisciplinary Research Team (BIRT) establishing collaboration in the fields of Tissue Engineering and Immunology. The synovial fluid of human joints normally functions biomechanically by lubricating articular cartilage, facilitating load-bearing and relative motion of apposing tissue surfaces with low friction and wear. In vivo, a deficiency in the lubricant function of synovial fluid may contribute to the cartilage erosion that occurs in post-injury degeneration, rheumatoid arthritis, and osteoarthritis. In vitro, a fluid with lubricant qualities like that of normal synovial fluid may be useful for engineering tissues in the form of cartilaginous or osteocartilaginous constructs including whole joints, when they are conditioned mechanically in a bioreactor by articulating motion. One component of synovial fluid that functions as a lubricant is hyaluronan (HA). The HA in synovial fluid is contributed primarily by the fibroblast-like synoviocytes of the synovial lining. In synovial fluids of injured and diseased joints, the decreased concentration and molecular weight of HA appear related to the elevated concentrations of certain cytokines. While HA secretion by fibroblast-like synoviocytes is regulated by IL-12 and TGF-21, the mechanisms of such regulation remain to be established. Knowledge of the immune regulation of HA secretion in vitro may facilitate the bioengineering of bioreactors to produce solutions that mimic the lubricant function and HA composition of native synovial fluid. The hypothesis of this study is that immune regulation, via IL-12 and TGF-21, of human synoviocyte HA secretion is through signaling pathways that modulate specific HA synthase enzymes, resulting in altered levels and molecular weight distributions of secreted HA, and, consequently, lubricant function. The associated aims are to assess (1) mechanisms of IL-12 and TGF-21 regulation of HA secretion in human synoviocytes by assessing HA synthase (HAS) mRNA, HAS protein, and HAS intracellular trafficking, after stimulation with cytokines, individually and in combination, and with inhibitors of selected signaling pathways, and (2) consequences of cytokine-regulated HA secretion in human synoviocytes by determining the molecular weight distribution and lubricating function of secreted HA in a "bioengineered synovial fluid."

描述（由申请人提供）：来自培养滑膜细胞的生物工程关节润滑剂本拟议修订旨在通过建立一个跨学科研究团队（BIRT），在组织工程和免疫学领域建立合作，以增加母基金NIH R 01 AR 051565关节软骨润滑机制。人类关节的滑液通常通过润滑关节软骨、促进具有低摩擦和磨损的并置组织表面的承载和相对运动而在生物力学上起作用。在体内，滑液的润滑功能的缺乏可能导致在损伤后变性、类风湿性关节炎和骨关节炎中发生的软骨侵蚀。在体外，具有类似于正常滑液的润滑性质的流体可用于工程化软骨或骨软骨构建体形式的组织，包括整个关节，当它们在生物反应器中通过关节运动机械调节时。作为润滑剂的滑液的一种组分是透明质酸（HA）。滑液中的HA主要由滑膜衬里的成纤维细胞样滑膜细胞贡献。在受伤和患病关节的滑液中，HA的浓度和分子量的降低似乎与某些细胞因子的浓度升高有关。虽然成纤维细胞样滑膜细胞的HA分泌受IL-12和TGF-21调节，但这种调节的机制仍有待建立。体外HA分泌的免疫调节知识可能有助于生物反应器的生物工程，以产生模拟天然滑液的润滑功能和HA组成的溶液。本研究的假设是，通过IL-12和TGF-21对人滑膜细胞HA分泌的免疫调节是通过调节特异性HA合酶的信号传导途径，导致分泌的HA的水平和分子量分布改变，从而导致润滑剂功能改变。相关的目的是评估（1）在用细胞因子单独和组合以及用所选信号传导途径的抑制剂刺激后，通过评估HA合酶（HAS）mRNA、HAS蛋白和HAS细胞内运输，IL-12和TGF-21调节人滑膜细胞中HA分泌的机制，和（2）通过测定“生物工程化滑液”中分泌的HA的分子量分布和润滑功能，研究人滑膜细胞中精氨酸调节的HA分泌的结果。"