Berberine Promotes Osteoblast Differentiation by Runx2 Activation With p38 MAPK

Abstract Berberine (BBR) has been implicated in bone biology. Although BBR reduces osteoporosis by enhancing BMD and inhibiting osteoclast activity, the effects of BBR on osteoblasts during the process of osteogenesis have not been thoroughly studied. In osteoblastic cells, BBR enhanced the expression of osteogenic marker genes including osteopontin and osteocalcin and promoted the transcriptional activity of the key osteogenic transcription factor Runx2. In osteoblasts, BBR increased the binding of Runx2 to the promoter region of osteopontin. The recruitment of co-factors such as p300 and HDAC1 to the promoter regions of osteopontin and osteocalcin was regulated by BBR, resulting in an enhancement in the expression of those genes. Furthermore, BBR activated p38 mitogen-activated protein kinase (MAPK) and increased cyclooxygenase 2 (COX2) expression, which are key factors in osteoblast differentiation. Consistently, a p38 MAPK-specific inhibitor attenuated the effect of BBR on osteogenesis, whereas p38 MAPK overexpression augmented BBR-induced osteogenic gene expression. Moreover, BBR stimulated bone area formation in calvarial organ culture. Taken together, these findings indicate that BBR promotes osteoblast differentiation through activation of Runx2 by p38 MAPK. Therefore, BBR may be a potential therapeutic agent to treat bone-related disorders including osteoporosis.