METTL3介导S1P通路m6A修饰调控早期OA软骨下骨重塑的机制研究

软骨下骨异常骨重塑是骨关节炎（OA）发病的重要因素。研究证明1-磷酸鞘氨醇（S1P）可调控骨重塑过程。本项目前期实验发现：OA软骨下骨S1P通路m6A甲基化水平显著升高，m6A相关酶中甲基转移酶METTL3特异性高表达，且METTL3可作用于S1P裂解酶（SPGL）。结合最新文献，我们提出假说：METTL3可介导S1P通路m6A甲基化调控软骨下骨骨重塑影响早期OA进展，此过程与软骨下骨中骨髓间充质干细胞的成骨分化密切相关。课题组拟利用高通量测序、CRISPR-Cas9基因编辑等前沿技术，锚定METTL3-SPGL1-S1P轴，通过临床样本检测、细胞实验和转基因动物模型系统阐释S1P通路调控软骨下骨重塑影响OA发病的机制。本项目聚焦软骨下骨异常骨重塑，交叉融通了磷脂代谢与表观遗传调控理论，有望为解析OA发病机制提供新证据，为OA治疗提供精准靶点。

Aberrant subchondral bone remodeling may be the initial factor of osteoarthritis (OA). It has been proved that sphingosine 1-phosphate (S1P) can balance the process of bone remodeling. In the previous experiment of this project, we found that the methylation level of m6A in S1P pathway of subchondral bone of OA was significantly increased, and METTL3 was highly expressed among m6A related enzymes. Moreover, METTL3 was closely linked to S1P lyase (SPGL) in experiments and informatics. We hypothesized that METTL3 mediates the methylation of m6A in S1P pathway to regulate the remodeling of subchondral bone, which may be related to the change of stem phenotype and osteogenic differentiation ability of BMSCs in subchondral bone. The research team are going to anchor METTL3-SPGL1-S1P axis by using cutting-edge technologies such as high-throughput sequencing, CRISPR-Cas 9 gene editing, and verified the scientific hypothesis through clinical sample testing, cell experiments and animal model evaluation. Through the cross fusion of subchondral bone, phospholipid metabolism and epigenetics, this project is expected to provide new evidence for clarifying the pathogenesis of OA and provide accurate targets for the epigenetic targeted therapy of OA.