Guanghua School of Stomatology, Hospital of Stomatology, Sun Yat-sen University, Guangzhou, China.
Guangdong Provincial Key Laboratory of Stomatology, Guangzhou, China.
FASEB J. 2021 Mar;35(3):e21283. doi: 10.1096/fj.202000373RRRR.
The pathological characteristics of osteoarthritis are cartilage matrix degradation, chondrocytes apoptosis, and low-grade inflammation of the joint. Recent studies have shown that blood vessels grow from the subchondral bone to the articular cartilage. However, the relationship among inflammation, angiogenesis, and chondrocyte apoptosis is still unclear. We found that chondrocytes could secrete chemokines and VEGF to promote the migration of vascular endothelial cells in response to TNF-α stimulation. The invasion of blood vessels leads to increased oxygen tension in the local environment, which increased the expression of SETD7 in chondrocytes by activating the JAK-STAT5 pathway. The bond of phosphorylated STAT5 and the specific locus in the promoter of SETD7 directly increased the transcription of SETD7. On the one hand, SETD7-regulated chemokine expression by forming a positive loop; on the other hand, SETD7-mediated chondrocyte apoptosis by inhibiting the nuclear localization of HIF-1α. In this study, we discovered a novel function of chondrocytes as mediators of inflammation and angiogenesis. Our study demonstrates that SETD7 is a potential molecular target to prevent OA development and progression.
骨关节炎的病理特征是软骨基质降解、软骨细胞凋亡和关节低度炎症。最近的研究表明，血管从软骨下骨向关节软骨生长。然而，炎症、血管生成和软骨细胞凋亡之间的关系仍不清楚。我们发现，软骨细胞可以分泌趋化因子和 VEGF，以响应 TNF-α刺激促进血管内皮细胞的迁移。血管的侵袭导致局部环境中氧分压增加，通过激活 JAK-STAT5 途径增加软骨细胞中 SETD7 的表达。磷酸化 STAT5 与 SETD7 启动子中特定位点的结合直接增加了 SETD7 的转录。一方面，SETD7 通过形成正反馈环调节趋化因子的表达；另一方面，SETD7 通过抑制 HIF-1α的核定位来介导软骨细胞凋亡。在这项研究中，我们发现了软骨细胞作为炎症和血管生成介质的新功能。我们的研究表明，SETD7 是预防 OA 发生和进展的潜在分子靶点。
