褪黑素在干细胞软骨再生中的抗炎/抗氧化作用及其对骨关节炎治疗的研究

Regeneration based stem cells is diffusely used in treatment of repairing bone injury or osteoarthritis. However, the microenvironment of hyperinflammatory, high free radical oxidation, proteolytic enzymes in osteoarthritis inhibited tissue engineering process, which leads vicious cycle of damaging - repairing - damaging. The team propose to use melatonin as an anti-inflammatory/anti-oxidant drug to provide a healthy environment for stem cells to repair cartilage, which would enhance anti-inflammatory in mesenchymal stem cells and hinder degradation in the new cartilages. The project intends to simulate osteoarthritis microenvironment adopting the primary inflammatory cytokine to reveal the mechanism of oxidative damage in stem cells, clarify melatonin's influence on cell proliferation, anti-oxidant and cartilage differentiation, and reveal the mechanisms of matrix proteolytic enzymes generation and new cartilage degradation by melatonin, which would advance cartilage damage repairing by stem cells.The results will perfect the osteoarthritis pathogenesis to provid effective method for tissue engineering in clinical treatment. It also offers ideas to develop biomaterials which is anti-inflammatory and pro-regenerative function for cartilage tissue engineering.The study would accelerate clinical applications of stem cell regenerative.

干细胞组织再生技术已广泛应用于骨修复和关节炎治疗中，但是关节炎造成高炎症因子、高氧化自由基、高蛋白水解酶的微环境抑制干细胞组织修复进程，易导致破坏-修复-破坏的恶性循环。课题组提出利用褪黑素抗炎性抗氧化功能为干细胞软骨修复提供健康微环境，望增强间充质干细胞的抗炎性和新生软骨的抗降解性。本项目拟采用骨性关节炎重要炎症因子模拟关节腔炎症微环境，揭示炎症因子加重干细胞氧化损伤进而降低再生能力的机理，阐明褪黑素对干细胞增殖、抗氧化及定向软骨分化能力影响，揭示褪黑素调控基质蛋白水解酶生成和新生软骨降解的分子机制，提高干细胞修复关节炎软骨损伤的治疗效果。研究成果将在理论上完善骨性关节炎的发病机理，为临床上改进干细胞治疗提供明确的思路，且为后续开发具有抗炎性和促再生功能的软骨组织工程材料提供思路，加快干细胞再生医学技术的临床应用。

骨关节炎造成高炎症因子、高氧化自由基、高蛋白水解酶的微环境抑制干细胞组织修复进程，易导致破坏-修复-破坏的恶性循环。本项目利用褪黑素抗炎性抗氧化功能为间充质干细胞软骨修复提供健康微环境，增强间充质干细胞的抗炎性和新生软骨的抗降解性。本项目模拟关节腔炎症微环境，体内体外试验 1）揭示炎症细胞因子(IL-1β/ TNF-α)通过破坏滑膜间充质干细胞抗氧化体系进而促进干细胞凋亡和阻碍软骨分化的分子机理；2）阐明褪黑素调控细胞生物抗氧化抗炎性功能，从而增强干细胞软骨修复效果的规律；3）阐明褪黑素调控MMPs表达，对新生软骨基质降解的分子机理；4）体外骨性关节炎模型构建及褪黑素、干细胞修复试验完成，可为开发利用褪黑素增强干细胞修复关节炎软骨损伤的新治疗技术，为后续软骨组织材料支架研发奠定基础。研究成果将在理论上完善骨性关节炎的发病机理，为临床上改进干细胞治疗提供明确的思路，且为后续开发具有抗炎性和促再生功能的软骨组织工程材料提供思路，加快干细胞再生医学技术的临床应用。