镁通过调控LncRNA MEG3抑制VEGF表达对骨关节炎的作用机制研究

Osteoarthritis (OA) is a common joint degenerative disease, and there is still no safe and effective early prevention and treatment. Previous studies and applicant’s previous research found that blood magnesium concentration was negatively correlated with knee OA prevalence. Magnesium supplementation can delay articular cartilage degeneration in rat OA model; magnesium can up-regulate lncRNA MEG3 expression in chondrocytes, and MEG3 can delay OA progression, suggesting that MEG3 might involve in the protective role of magnesium. Another study found that magnesium can down-regulate the expression of VEGF in cerebrospinal fluid and chondrocytes; MEG3 can down-regulate the expression of VEGF in brain tissue, and it is negatively correlated with the expression of VEGF in cartilage; VEGF plays an important role in the pathological process of OA. Combined, the applicant speculates that magnesium may prevent and cure OA by downregulating the expression of VEGF through increasing the expression of MEG3. This project aims to do experiments to elucidate how magnesium could facilitate the inhibition of VEGF expression through upregulation of MEG3 to delay cartilage degradation on both cells in vitro and animal models by using techniques such as overexpression transfection, siRNA interference, qRT-PCR and Western Blot, trying to provide a novel alternative strategy for clinical OA prevention and treatment.

骨关节炎（osteoarthritis, OA）是常见关节退行性疾病，尚缺乏安全有效的早期防治手段。既往研究和申请人研究发现：血镁浓度与膝OA患病率呈负相关，镁补充可延缓大鼠OA模型关节软骨退变；镁可上调软骨细胞lncRNA MEG3表达，MEG3可延缓OA进展。提示镁可通过MEG3影响OA发生发展。另有研究发现：镁可下调脑脊液和软骨细胞VEGF表达；MEG3可下调脑组织VEGF表达，且在软骨中与VEGF表达水平呈负相关；VEGF在OA病理过程中起到重要作用。提示镁可通过调控MEG3进而抑制VEGF最终影响OA发生发展。本项目拟采用过表达转染和siRNA干扰等技术，在体外细胞和模式动物两个层面明确镁通过上调软骨细胞MEG3表达水平，进而抑制VEGF表达，最终延缓关节软骨退变，并进一步探索MEG3调控VEGF表达过程的关键因子。

骨关节炎是一种常见的退行性骨关节疾病，国内外尚无安全有效的早期干预措施，明确其危险因素对探寻有效且经济实惠的早期干预方式具有重要意义。既往人群研究表明低镁为骨关节炎患病的危险因素，提示较低水平的膳食镁摄入水平可能为膝骨关节炎患病的危险因素，课题组前期研究发现低镁可通过抑制自噬加重骨关节炎病情变化。本项目在上述研究基础上通过动物实验证实膳食镁对骨关节炎滑膜炎症和疼痛症状的影响，研究镁对骨关节炎进展的作用和潜在机制，发现低镁膳食可缓解骨关节炎滑膜炎症和疼痛症状。本项目进一步开展机制研究，发现母系表达基因3（maternally expressed gene 3, MEG3）可通过下调血管内皮生长因子（vascular endothelial growth factor, VEGF）表达，介导镁对骨关节炎的作用。本项目为研究镁补充治疗骨关节炎制提了供新的理论依据，也为探索骨关节炎干预靶点和防治措施提供了新思路。