Osthole Enhances Osteogenesis in Osteoblasts by Elevating Transcription Factor Osterix via cAMP/CREB Signaling In Vitro and In Vivo

• Published in: Nutrients 2017-06, Vol.9 (6), p.588
• Main Authors: Zhang, Zhong-Rong, Leung, Wing Nang, Li, Gang, Kong, Siu Kai, Lu, Xiong, Wong, Yin Mei, Chan, Chun Wai
• Format: Article
• Language: English
• Subjects: Activation; Adenosine monophosphate; Alkaline phosphatase; Alkaline Phosphatase - drug effects; Alkaline Phosphatase - metabolism; Animals; Biocompatibility; Biomedical materials; Bone strength; Calcium Channel Blockers - pharmacology; Cell Line; Cell Proliferation; Cell Survival; Coumarin; Coumarins - pharmacology; CREB-Binding Protein - genetics; CREB-Binding Protein - metabolism; Cyclic AMP - metabolism; Cyclic AMP response element-binding protein; Enzyme inhibitors; Femur; Fractures; Fragility; Gene Expression Regulation - drug effects; Herbal medicine; Kinases; Male; Medicinal herbs; Mice; Mice, Inbred C57BL; Mineralization; Osteoblasts; Osteoblasts - drug effects; Osteogenesis; Osteogenesis - drug effects; Osteoporosis; Phosphorylation; Protein kinase A; Proteins; Repair; Signal transduction; Sp7 Transcription Factor - genetics; Sp7 Transcription Factor - metabolism; Transcription factors
• ISSN: 2072-6643; 2072-6643
• DOI: 10.3390/nu9060588

Anabolic anti-osteoporotic agents are desirable for treatment and prevention of osteoporosis and fragility fractures. Osthole is a coumarin derivative extracted from the medicinal herbs (L.) Cusson and Maxim.f. Osthole has been reported with osteogenic and anti-osteoporotic properties, whereas the underlying mechanism of its benefit still remains unclear. The objective of the present study was to investigate the osteopromotive action of osthole on mouse osteoblastic MC3T3-E1 cells and on mouse femoral fracture repair, and to explore the interaction between osthole-induced osteopromotive effect and cyclic adenosine monophosphate (cAMP) elevating effect. Osthole treatment promoted osteogenesis in osteoblasts by enhancing alkaline phosphatase (ALP) activity and mineralization. Oral gavage of osthole enhanced fracture repair and increased bone strength. Mechanistic study showed osthole triggered the cAMP/CREB pathway through the elevation of the intracellular cAMP level and activation of the phosphorylation of the cAMP response element-binding protein (CREB). Blockage of cAMP/CREB downstream signals with protein kinase A (PKA) inhibitor KT5720 partially suppressed osthole-mediated osteogenesis by inhibiting the elevation of transcription factor, osterix. In conclusion, osthole shows osteopromotive effect on osteoblasts in vitro and in vivo. Osthole-mediated osteogenesis is related to activation of the cAMP/CREB signaling pathway and downstream osterix expression.