Epoxyeicosanoids suppress osteoclastogenesis and prevent ovariectomy-induced bone loss
Epoxyeicosanoids suppress osteoclastogenesis and prevent ovariectomy-induced bone loss
复制标题
环氧类二十烷酸抑制破骨细胞生成并防止卵巢切除术引起的骨质流失。
DOI：
10.1096/fj.14-262055
复制
发表时间：
2015-03-01
期刊：
影响因子：
4.8
通讯作者：
Xiao, Jun
中科院分区：
文献类型：
--
作者：
Guan, Hanfeng;Zhao, Libo;Xiao, Jun
环氧二十碳三烯酸(EETs)是细胞色素P450环氧酶催化花生四烯酸代谢的产物。这些小分子是自分泌和旁分泌的脂质介质，在炎症、心血管功能和血管生成中发挥重要作用。最近的证据表明，EETs是器官再生和恶性转移的有力促进剂。我们推测EETs可能影响破骨细胞的形成和骨丢失。利用体外和体内研究，我们观察到EETs显著减轻骨丢失，抑制破骨细胞的形成和活性，这与核因子-kappa B配体受体激活物(RANKL)：护骨素比率和血清中TNF-α和IL-1β水平的降低有关。在分子水平上，在破骨细胞形成过程中，EETs抑制了RANKL诱导的NF-kappa B、激活蛋白-1(AP-1)和包括ERK和JNK在内的MAPK的激活，但不能抑制p38的激活。EETs还可防止RANKL刺激后产生的活性氧(ROS)。因此，EETs抑制破骨细胞特异性基因的表达，包括抗酒石酸酸性磷酸酶(TRAP)、组织蛋白酶K(CK)、基质金属蛋白酶(MMP)-9和核因子-kappaB受体激活剂(RANK)。综上所述，我们的研究结果表明，EETs通过调节RANKL信号的上游和下游的多条途径来抑制破骨细胞的形成。给予或稳定内源性EETs水平可能代表着一种治疗破骨细胞相关疾病的新策略，如类风湿性关节炎和绝经后骨质疏松症。
Epoxyeicosatrienoic acids (EETs) are products of arachidonic acid metabolism catalyzed by cytochrome P450 epoxygenases. These small molecules are autocrine and paracrine lipid mediators with important roles in inflammation, cardiovascular function, and angiogenesis. Recent evidence has highlighted EETs as potent promoters of organ regeneration and malignant metastasis. We speculated that EETs might impact osteoclastogenesis and bone loss. Using both in vitro and in vivo studies, we observed that EETs significantly attenuated bone loss and inhibited osteoclast formation and activity, which were associated with a decreased receptor activator of NF-kappa B ligand (RANKL): osteoprotegerin ratio and serum levels of TNF-alpha and IL-1 beta. At the molecular level, EETs abrogated RANKL-induced activation of NF-kappa B, activator protein-1 (AP-1), and MAPKs, including ERK and JNK, but not p38, during osteoclast formation. EETs also prevented the production of reactive oxygen species (ROS) following RANKL stimulation. As a result, EETs suppressed osteoclast-specific gene expression, including tartrate resistant acid phosphatase (TRAP), cathepsin K (CK), matrix metalloproteinase (MMP)-9, and receptor activator of NF-kappa B (RANK). In conclusion, our findings demonstrate that EETs inhibit osteoclastogenesis through modulation of multiple pathways both upstream and downstream of RANKL signaling. The administration or stabilized endogenous levels of EETs could represent a novel therapeutic strategy for osteoclast-related disorders, such as rheumatoid arthritis and postmenopausal osteoporosis.