Estrogen preserves Fas ligand levels by inhibiting microRNA-181a in bone marrow-derived mesenchymal stem cells to maintain bone remodeling balance
Estrogen preserves Fas ligand levels by inhibiting microRNA-181a in bone marrow-derived mesenchymal stem cells to maintain bone remodeling balance
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雌激素通过抑制骨髓间充质干细胞中的 microRNA-181a 来保持 Fas 配体水平，以维持骨重塑平衡
DOI：
10.1096/fj.15-272823
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发表时间：
2015-09-01
期刊：
影响因子：
4.8
通讯作者：
Jin, Yan
中科院分区：
文献类型：
--
作者：
Shao, Bingyi;Liao, Li;Jin, Yan
雌激素通过促进破骨细胞和成骨细胞Fas配体（FasL）的转录，诱导破骨细胞凋亡，从而保护骨丢失。骨髓间充质干细胞（BMMSCs）表达FasL蛋白，其在细胞治疗中诱导T细胞凋亡是必需的。然而，FasL在BMMSCs中的生理功能尚不清楚。在这项研究中，我们使用体外共培养系统和体内BMMSC移植实验，我们发现BMMSC通过FasL/Fas途径有效地诱导破骨细胞凋亡。雌激素作为FasL蛋白在BMMSCs中积累的启动子，在这一过程中是必需的。此外，雌激素增加FasL蛋白的积累，而不是通过增加FasL基因的转录，但通过microRNA介导的转录后调节。简而言之，雌激素下调miR-181 a的表达，miR-181 a是一种靶向FasL mRNA的3 '-UTR的FasL负调节剂。雌激素缺乏导致过量的miR-181 a，其降低FasL蛋白水平以抑制BMMSC诱导的破骨细胞凋亡。此外，miR-181 a的敲低恢复了雌激素缺乏时BMMSC诱导破骨细胞凋亡的缺陷。综上所述，我们的研究结果表明，雌激素通过抑制BMMSCs中miR-181 a的表达来维持FasL蛋白的积累，以维持骨重建平衡，这表明雌激素保护骨量的新机制。
Estrogen protects bone loss by promoting Fas ligand (FasL) transcription in osteoclasts and osteoblasts to induce apoptosis of osteoclasts. Bone marrow-derived mesenchymal stem cells (BMMSCs) express FasL protein, which is necessary for BMMSCs to induce T-cell apoptosis in cell therapy. However, the physiologic function of FasL in BMMSCs is unknown. In this study, using an in vitro coculture system and an in vivo BMMSC transplantation assay, we found that BMMSCs potently induced apoptosis of osteoclasts through the FasL/Fas pathway. Estrogen was necessary for this process as a promoter of FasL protein accumulation in BMMSCs. Furthermore, estrogen elevated FasL protein accumulation, not by increasing FasL gene transcription, but through microRNA-mediated posttranscriptional regulation. In brief, estrogen down-regulated expression of miR-181a, a negative modulator of FasL targeting the 3'-UTR of FasL mRNA. Estrogen deficiency resulted in excessive miR-181a, which decreased FasL protein levels to suppress BMMSC-induced osteoclast apoptosis. Furthermore, knockdown of miR-181a recovered the BMMSC defect to induce osteoclast apoptosis during estrogen deficiency. Taken together, our results showed that estrogen preserves FasL protein accumulation by inhibiting miR-181a expression in BMMSCs to maintain bone remodeling balance, suggesting a novel mechanism by which estrogen preserves bone mass.