Berberine Derivative Compound 13 as a Potent Promoter of Osteoblast Differentiation via Akt and PKC Signaling Pathways

Berberine has been widely studied for its biological functions in various diseases, including cancer, diabetes, and cardiovascular diseases. Nevertheless, structural modifications of berberine have been demonstrated to augment its pharmacological efficacy in specific biological processes, particularly osteogenesis. In this study, we aimed to explore new berberine derivatives with pro-osteogenic activity and molecular mechanisms. Our results demonstrated that compound <b>13</b> is the most effective among the tested compounds. Compound <b>13</b> significantly enhanced BMP4-induced alkaline phosphatase (ALP) staining and increased the transcriptional activity of osteogenic markers such as ALP, Runt-related gene 2 (Runx2), and Osterix at both the mRNA and protein levels. Furthermore, we found that the Akt and PKC signaling pathways play crucial roles in compound <b>13</b>-induced osteogenesis via treatment with specific inhibitors. The molecular docking results supported the potential interaction between compound <b>13</b> and these kinases. These findings highlighted the regulatory role of compound <b>13</b> in osteoblast differentiation via the Akt and PKC signaling pathways. Overall, our study provides compelling evidence that compound <b>13</b> is a promising therapeutic candidate for the treatment of osteoporosis, with the potential for further development and optimization to improve bone health and strength.