Bisphenol A inhibits osteogenic activity and causes bone resorption via the activation of retinoic acid-related orphan receptor α

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.