Osthole stimulates osteoblast differentiation and bone formation by activation of β-catenin–BMP signaling

Abstract

Osteoporosis is defined as reduced bone mineral density with a high risk of fragile fracture. Current available treatment regimens include antiresorptive drugs such as estrogen receptor analogues and bisphosphates and anabolic agents such as parathyroid hormone (PTH). However, neither option is completely satisfactory because of adverse effects. It is thus highly desirable to identify novel anabolic agents to improve future osteoporosis treatment. Osthole, a coumarin-like derivative extracted from Chinese herbs, has been shown to stimulate osteoblast proliferation and differentiation, but its effect on bone formation in vivo and underlying mechanism remain unknown. In this study, we found that local injection of Osthole significantly increased new bone formation on the surface of mouse calvaria. Ovariectomy caused evident bone loss in rats, whereas Osthole largely prevented such loss, as shown by improved bone microarchitecture, histomorphometric parameters, and biomechanical properties. In vitro studies demonstrated that Osthole activated Wnt/β-catenin signaling, increased Bmp2 expression, and stimulated osteoblast differentiation. Targeted deletion of the β-catenin and Bmp2 genes abolished the stimulatory effect of Osthole on osteoblast differentiation. Since deletion of the Bmp2 gene did not affect Osthole-induced β-catenin expression and the deletion of the β-catenin gene inhibited Osthole-regulated Bmp2 expression in osteoblasts, we propose that Osthole acts through β-catenin–BMP signaling to promote osteoblast differentiation. Our findings demonstrate that Osthole could be a potential anabolic agent to stimulate bone formation and prevent estrogen deficiency–induced bone loss. © 2010 American Society for Bone and Mineral Research.

An Inhibitory Role of Osthole in Rat MSCs Osteogenic Differentiation and Proliferation via Wnt/β-Catenin and Erk1/2-MAPK Pathways

“…It has been reported that Osthole promoted the differentiation and maturation of osteoblasts [11][12][13][14]. However, our observations in this study seem controdictory to other reported findings, which are as follows: Firstly, the MSC proliferation was inhibited by Osthole.…”

Daidzein promotes osteoblast proliferation and differentiation in OCT1 cells through stimulating the activation of BMP-2/Smads pathway

“…Phosphorylated Smad1/5/8 and Smad4 forms a protein complex, translocates into the nucleus to activate the bone-specific-genes transcription, which in turn promote osteoblast differentiation (Sykaras and Opperman, 2003;Chen et al, 2004;Miyazono et al, 2005;Wan and Cao, 2005;Bilican et al, 2008). As a matter of fact, it has been reported that several small molecular weight compounds can be able to activate BMP-2 signaling (Mundy et al, 1999;Garrett et al, 2003;Tang et al, 2010;Tang et al, 2011;Li et al, 2013). To clarify the mechanism by which daidzein promotes the cell proliferation and differentiation of osteoblast, we tested if it can activate BMP-2 signaling.…”

Osthole Exhibits Anti-Cancer Property in Rat Glioma Cells Through Inhibiting PI3K/Akt and MAPK Signaling Pathways

“…We first evaluated the proliferation of C6 glioma cells between Osthole-treated groups and control group by using different methods. It was reported that Osthole did not display any cell toxicity in normal osteoblasts even at the concentration of 100 μM [22]. Meanwhile, combined with the concentration of Osthole used in other tumor [12,23], C6 cells were treated with different concentrations of Osthole (0-100 μM) for different time points.…”