镁离子调节关节软骨内干细胞软骨分化活性以治疗骨关节炎的机制研究

It had been reported that there are stem cells/progenitors in articular cartilage tissue in many recent researches, however, the origins of the cartilage stem cells are not known yet. In the processing of osteoarthritis (OA), the cartilage stem cells are losing their chondrogenic differentiating ability due to the lasting chronic inflammation. That is why the current anti-OA pharmaceuticals have only restricted effect in OA treatment. Recently, we found that injection of magnesium ions in the articular cavity could effectively renovate the tissue lesion in rat OA. As a pivotal element in cartilage tissue metabolism, magnesium ions were found significantly maintained the normal cell morphology and chondrogenic differentiating ability of BMSCs in a long period, meanwhile, cellular ATP content was elevated significantly after magnesium ions entering stem cells. However, the mechanism is unknown. We make hypotheses that magnesium could increase cellular ATP content through affecting energy metabolism pathway. The cellular ATP inhibit p21（CIP1） expression, then SOX2 will be upregulated and activated which maintaining the pluripotency of stem cells. In this proposal, we will study the mechanism of magnesium’ revitalizing effect on stem cells by the experiments in vitro and in vivo with double transgenic mice, nude mice and S/D rats OA model. We will make hydrogel containing nano-scaled magnesium metal powder or magnesium oxide powder to effectively repair the cartilage through controlled-releasing of magnesium ions in the OA treatment.

研究表明软骨组织内存在修复受损组织的干细胞，在骨关节炎（OA）中，软骨内干细胞逐渐失去分化能力。镁离子是维持软骨功能和代谢的重要元素，关节腔补充镁离子能够促进大鼠OA软骨组织内干细胞向软骨方向分化，修复透明软骨组织，缓解OA病变。体外实验结果表明镁离子可长时间维持骨髓间充质干细胞形态和成软骨分化潜力，同时干细胞内ATP含量显著上升，其机制不明。我们推测镁离子通过调控干细胞能量代谢过程，增加胞内ATP含量，进而抑制细胞周期蛋白p21（CIP1）的表达，最后促进干细胞多能性的重要调节因子SOX2的上调和活性，从而保持干细胞软骨分化活性。本课题将从细胞和动物模型两个层面，探索镁离子通过调节软骨组织内干细胞软骨分化最终治疗骨关节炎的有效性。针对镁盐溶液关节腔注射的缺点，我们制备透明质酸水凝胶包裹纳米镁金属颗粒，缓释镁离子以达到更好的OA治疗效果。

研究表明软骨组织内存在修复受损组织的软骨细胞，在骨关节炎（OA）中，软骨细胞逐渐失去正常的软骨细胞外基质合成能力。镁离子是维持软骨功能和代谢的重要元素，关节腔补充镁离子能够促进大鼠OA软骨组织内软骨细胞维持活性，修复透明软骨组织，缓解OA病变。体外实验结果表明镁离子可长时间维持骨髓间充质干细胞形态和成软骨分化潜力，同时干细胞内ATP含量显著上升，其机制不明。我们的研究发现镁离子通过抑制软骨细胞的PI3K-AKT信号通道，进而抑制软骨细胞在炎性环境下的凋亡。本课从细胞和动物模型两个层面，探索镁离子通过抑制软骨组织内软骨细胞凋亡最终治疗骨关节炎的有效性。针对镁盐溶液关节腔注射的缺点，我们制备了PLGA微球包裹纳米氧化镁颗粒，缓释镁离子以达到更好的OA治疗效果。