Dual targeting of SREBP2 and ERRα by carnosic acid suppresses RANKL-mediated osteoclastogenesis and prevents ovariectomy-induced bone loss.,Cell Death and Differentiation

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Dual targeting of SREBP2 and ERRα by carnosic acid suppresses RANKL-mediated osteoclastogenesis and prevents ovariectomy-induced bone loss.
Cell Death and Differentiation ( IF 13.7 ) Pub Date : 2020-01-06 , DOI: 10.1038/s41418-019-0484-5
Zu-Guo Zheng ₁ , Hui-Min Cheng ₁ , Ya-Ping Zhou ₁ , Si-Tong Zhu ₁ , Pyone Myat Thu ₁ , Hui-Jun Li ₁ , Ping Li ₁ , Xiaojun Xu _{1,

2}

Affiliation

Osteoporosis develops because of impaired bone formation and/or excessive bone resorption. Several pharmacological treatment of osteoporosis has been developed; however, new treatments are still necessary. Cholesterol and estrogen receptor-related receptor alpha (ERRα) promote osteoclasts formation, survival, and cellular fusion and thus become high risk factors of osteoporosis. In this study, we identified that carnosic acid (CA) suppressed bone loss by dual-targeting of sterol regulatory element-binding protein 2 (SREBP2, a major regulator that regulates cholesterol synthesis) and ERRα. Mechanistically, CA reduced nuclear localization of mature SREBP2 and suppressed de novo biogenesis of cholesterol. CA subsequently decreased the interaction between ERRα and peroxisome proliferator-activated receptor gamma coactivator 1-beta (PGC1β), resulting in decreased the transcription activity of ERRα and its target genes expression. Meanwhile, CA directly bound to the ligand-binding domain of ERRα and significantly promoted its ubiquitination and proteasomal degradation. Subsequently, STUB1 was identified as the E3 ligase of ERRα. The lysine residues (K51 and K68) are essential for ubiquitination and proteasomal degradation of ERRα by CA. In conclusion, CA dually targets SREBP2 and ERRα, thus inhibits the RANKL-induced osteoclast formation and improves OVX-induced bone loss. CA may serve as a lead compound for pharmacological control of osteoporosis.

中文翻译：

鼠尾草酸双重靶向 SREBP2 和 ERRα 可抑制 RANKL 介导的破骨细胞生成，并防止卵巢切除术引起的骨质流失。

骨质疏松症是由于骨形成受损和/或骨吸收过度而发生的。已经开发出几种治疗骨质疏松症的药物；然而，仍然需要新的治疗方法。胆固醇和雌激素受体相关受体α（ERRα）促进破骨细胞的形成、存活和细胞融合，从而成为骨质疏松症的高危因素。在这项研究中，我们发现鼠尾草酸 (CA) 通过双重靶向甾醇调节元件结合蛋白 2（SREBP2，调节胆固醇合成的主要调节因子）和 ERRα 来抑制骨质流失。从机制上讲，CA 减少了成熟 SREBP2 的核定位并抑制了胆固醇的从头生物发生。 CA 随后降低了 ERRα 与过氧化物酶体增殖物激活受体 γ 共激活因子 1-β (PGC1β) 之间的相互作用，导致 ERRα 的转录活性及其靶基因表达降低。同时，CA直接与ERRα的配体结合域结合，显着促进其泛素化和蛋白酶体降解。随后，STUB1被鉴定为ERRα的E3连接酶。赖氨酸残基（K51 和 K68）对于 CA 对 ERRα 的泛素化和蛋白酶体降解至关重要。总之，CA双重靶向SREBP2和ERRα，从而抑制RANKL诱导的破骨细胞形成并改善OVX诱导的骨丢失。 CA可以作为药物控制骨质疏松症的先导化合物。

更新日期：2020-01-06

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