MFG-E8 regulated by miR-99b-5p protects against osteoarthritis by targeting chondrocyte senescence and macrophage reprogramming via the NF-κB pathway.
MFG-E8 regulated by miR-99b-5p protects against osteoarthritis by targeting chondrocyte senescence and macrophage reprogramming via the NF-κB pathway.
复制标题
受 miR-99b-5p 调节的 MFG-E8 通过 NF-κB 途径靶向软骨细胞衰老和巨噬细胞重编程，从而预防骨关节炎。
DOI：
10.1038/s41419-021-03800-x
复制
发表时间：
2021-05-25
影响因子：
9
通讯作者：
Cai D
中科院分区：
文献类型：
--
作者：
Lu Y;Liu L;Pan J;Luo B;Zeng H;Shao Y;Zhang H;Guan H;Guo D;Zeng C;Zhang R;Bai X;Zhang H;Cai D
乳脂球-表皮生长因子8(MFG-E8)作为细胞凋亡和吞噬细胞之间的必要桥梁分子，在多种器官和疾病中得到了广泛的研究，但其在骨关节炎(OA)中的作用尚不清楚。在这里，我们确定MFG-E8是介导软骨细胞衰老和巨噬细胞极化的关键因子，并揭示了它在骨关节炎病理中的作用。我们发现，随着骨性关节炎患者和小鼠内侧半月板手术(DMM)诱发骨性关节炎的失稳，随着骨性关节炎的进展，MFG-E8的表达在局部和全身性下调。MFG-E8缺失可引起骨关节炎小鼠关节软骨进行性损伤、滑膜增生和大量骨赘形成，经关节腔注射重组小鼠MFG-E8(rmMFG-E8)可缓解这一现象。此外，MFG-E8恢复了软骨细胞的动态平衡，延缓了软骨细胞的衰老，并将巨噬细胞重新编程为M2亚型以减轻OA。进一步研究表明，miR-99b-5p可抑制MFG-E8在软骨中的表达，部分通过激活软骨细胞中的NF-κB信号，导致实验性骨性关节炎的加重。我们的发现证实了MFG-E8在骨性关节炎软骨细胞衰老和巨噬细胞重编程中的重要作用，并确定关节内注射MFG-E8是预防和治疗骨性关节炎的潜在治疗靶点。
Milk fat globule-epidermal growth factor (EGF) factor 8 (MFG-E8), as a necessary bridging molecule between apoptotic cells and phagocytic cells, has been widely studied in various organs and diseases, while the effect of MFG-E8 in osteoarthritis (OA) remains unclear. Here, we identified MFG-E8 as a key factor mediating chondrocyte senescence and macrophage polarization and revealed its role in the pathology of OA. We found that MFG-E8 expression was downregulated both locally and systemically as OA advanced in patients with OA and in mice after destabilization of the medial meniscus surgery (DMM) to induce OA. MFG-E8 loss caused striking progressive articular cartilage damage, synovial hyperplasia, and massive osteophyte formation in OA mice, which was relieved by intra-articular administration of recombinant mouse MFG-E8 (rmMFG-E8). Moreover, MFG-E8 restored chondrocyte homeostasis, deferred chondrocyte senescence and reprogrammed macrophages to the M2 subtype to alleviate OA. Further studies showed that MFG-E8 was inhibited by miR-99b-5p, expression of which was significantly upregulated in OA cartilage, leading to exacerbation of experimental OA partially through activation of NF-κB signaling in chondrocytes. Our findings established an essential role of MFG-E8 in chondrocyte senescence and macrophage reprogramming during OA, and identified intra-articular injection of MFG-E8 as a potential therapeutic target for OA prevention and treatment.
登录
查看更多内容
影响因子：
9
作者：
Gao YY;Zhang ZH;Zhuang Z;Lu Y;Wu LY;Ye ZN;Zhang XS;Chen CL;Li W;Hang CH
通讯作者：
Hang CH
DOI：
10.18632/aging.101328
发表时间：
2017-11-22
期刊：
Aging
影响因子：
--
作者：
Kandhaya-Pillai R;Miro-Mur F;Alijotas-Reig J;Tchkonia T;Kirkland JL;Schwartz S
通讯作者：
Schwartz S
影响因子：
27.4
作者：
Atukorala I;Kwoh CK;Guermazi A;Roemer FW;Boudreau RM;Hannon MJ;Hunter DJ
通讯作者：
Hunter DJ
影响因子：
--
作者：
Ekenstedt, Kari J.;Sonntag, William E.;Carlson, Cathy S.
通讯作者：
Carlson, Cathy S.
影响因子：
2.2
作者：
Feng, Guijuan;Zheng, Ke;Feng, Xingmei
通讯作者：
Feng, Xingmei