Zhang Zhong-Rong, Leung Wing Nang, Li Gang, Kong Siu Kai, Lu Xiong, Wong Yin Mei, Chan Chun Wai
School of Chinese Medicine, Faculty of Medicine, The Chinese University of Hong Kong, Shatin, Hong Kong, China.
Department of Orthopaedics and Traumatology, Faculty of Medicine, The Chinese University of Hong Kong, Shatin, Hong Kong, China.
Nutrients. 2017 Jun 8;9(6):588. 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.
合成代谢抗骨质疏松药物对于骨质疏松症和脆性骨折的治疗及预防而言是理想的。蛇床子素是从蛇床（学名：Cnidium monnieri (L.) Cusson）和兴安蛇床（学名：Cnidium dahuricum Maxim.f.）等草药中提取的一种香豆素衍生物。据报道，蛇床子素具有成骨和抗骨质疏松特性，但其有益作用的潜在机制仍不清楚。本研究的目的是研究蛇床子素对小鼠成骨细胞MC3T3-E1细胞和小鼠股骨骨折修复的促骨生成作用，并探讨蛇床子素诱导的促骨生成作用与环磷酸腺苷（cAMP）升高作用之间的相互作用。蛇床子素处理通过增强碱性磷酸酶（ALP）活性和矿化作用促进成骨细胞的成骨作用。口服灌胃蛇床子素可增强骨折修复并提高骨强度。机制研究表明，蛇床子素通过提高细胞内cAMP水平和激活cAMP反应元件结合蛋白（CREB）的磷酸化来触发cAMP/CREB信号通路。用蛋白激酶A（PKA）抑制剂KT5720阻断cAMP/CREB下游信号，通过抑制转录因子osterix的升高，部分抑制了蛇床子素介导的成骨作用。总之，蛇床子素在体外和体内均对成骨细胞显示出促骨生成作用。蛇床子素介导的成骨作用与cAMP/CREB信号通路的激活及下游osterix表达有关。
