Abstract
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 Cnidium monnieri (L.) Cusson and Angelica pubescens 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.
Highlights
Osteoporosis is a systemic skeletal disease characterized by impairment of bone mineral density, strength, and microstructure, leading to an increased risk of fragility fracture that can cause substantial morbidity and mortality [1]
Osthole did not lead to MTT results demonstrated that osthole inhibited the proliferation of MC3T3-E1 cells in a timesignificant inhibition on cell proliferation at concentrations less than 100 μM
We found that osthole treatment mediated osteogenesis it promoted osteogenic differentiation, which was consistent with previous findings in otherin osteoblasts in vitro, enhanced the ossification process not in vivo, resulted in faster bone osteoblastic-like cells.but
Summary
Osteoporosis is a systemic skeletal disease characterized by impairment of bone mineral density, strength, and microstructure, leading to an increased risk of fragility fracture that can cause substantial morbidity and mortality [1]. It has become a major public health problem worldwide along with the aging of the population [2]. Osteoporotic fracture treatment has particular difficulties with high rates of implant fixation failure and increased non-union risk caused by delayed bone formation [3,4,5]. Numerous bioactive phytochemicals found in functional and medicinal food are suggested to have anti-osteoporotic properties [13,14,15,16]
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