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 ROR alpha plays an important role in BPA-induced bone resorption both in vitro and in vivo. We found that BPA (0.1-1 mu M) 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 beta-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 ROR alpha-ligand binding domain with hydrogen bonding (ALA330 and/or ARG367 in the full length of ROR alpha, respectively), which another hydroxyl group of BPA fits into H3, H6, and H7 elements with non-covalent interactions, resulting in the activation of ROR alpha. However, an ROR alpha 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 ROR alpha. These results suggest that BPA exposure (0.1-1 mu M) can cause various bone-resorptive diseases, such as osteoporosis.

Automated summary

This study reveals that BPA inhibits osteoblast differentiation and bone formation by activating ROR alpha, potentially causing bone-resorptive diseases such as osteoporosis.