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Bisphenol A inhibits osteogenic activity and causes bone resorption via the activation of retinoic acid-related orphan receptor α
Journal of Hazardous Materials ( IF 13.6 ) Pub Date : 2022-06-26 , DOI: 10.1016/j.jhazmat.2022.129458
Wisurumuni Arachchilage Hasitha Maduranga Karunarathne 1 , Yung Hyun Choi 2 , Sang Rul Park 3 , Chang-Min Lee 4 , Gi-Young Kim 3
Affiliation  

Bisphenol A (BPA) has deleterious effects on bone metabolism; however, its underlying mechanism has not yet been comprehensively understood. Here, we investigated whether RORα plays an important role in BPA-induced bone resorption both in vitro and in vivo. We found that BPA (0.1–1 μM) inhibited osteogenic activity (including ALP activity and mineralization), decreased the expression levels of osteoblast markers (such as RUNX2, OSX, and ALP) in human MG-63 osteoblast-like osteosarcoma cells, and inhibited spontaneous vertebral formation in zebrafish larvae. Additionally, BPA diminished β-glycerophosphate-induced osteoblast differentiation and vertebral formation, while simultaneously downregulating the expression levels of RUNX2a, OSX, and ALP. Furthermore, molecular docking data showed that a hydroxyl group of BPA dominantly binds to the H3 (ALA70) and/or H5 (ARG107) of RORα-ligand binding domain with hydrogen bonding (ALA330 and/or ARG367 in the full length of RORα, respectively), which another hydroxyl group of BPA fits into H3, H6, and H7 elements with non-covalent interactions, resulting in the activation of RORα. However, an RORα inverse agonist potently inhibited BPA-induced anti-osteogenic activity and vertebral formation in zebrafish larvae, concomitant with inhibition of osteogenic gene expression. Overall, our findings reveal that BPA inhibits osteoblast differentiation and bone formation by activating RORα. These results suggest that BPA exposure (0.1–1 μM) can cause various bone-resorptive diseases, such as osteoporosis.



中文翻译:

双酚A通过激活视黄酸相关的孤儿受体α抑制成骨活性并引起骨吸收

双酚 A (BPA) 对骨代谢有有害影响;然而,其潜在机制尚未得到全面了解。在这里,我们研究了 RORα 是否在体外和体内双酚 A 诱导的骨吸收中起重要作用。我们发现 BPA (0.1–1 μM) 抑制成骨活性(包括 ALP 活性和矿化),降低人 MG-63 成骨样骨肉瘤细胞中成骨细胞标志物(如 RUNX2、OSX 和 ALP)的表达水平,以及抑制斑马鱼幼虫的自发椎体形成。此外,BPA 减少了 β-甘油磷酸盐诱导的成骨细胞分化和椎体形成,同时下调了RUNX2aOSXALP的表达水平. 此外,分子对接数据显示,BPA 的羟基主要与 RORα 配体结合结构域的 H3 (ALA70) 和/或 H5 (ARG107) 结合,分别在全长 RORα 中具有氢键(ALA330 和/或 ARG367) ),BPA 的另一个羟基与 H3、H6 和 H7 元素具有非共价相互作用,导致 RORα 的活化。然而,RORα 反向激动剂在斑马鱼幼虫中有效抑制 BPA 诱导的抗成骨活性和椎骨形成,同时抑制成骨基因表达。总体而言,我们的研究结果表明,BPA 通过激活 RORα 抑制成骨细胞分化和骨形成。这些结果表明,BPA 暴露(0.1-1 μM)会导致各种骨吸收性疾病,例如骨质疏松症。

更新日期:2022-06-26
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