Osthole stimulates osteoblast differentiation and bone formation by activation of beta-catenin-BMP signaling.
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/beta-catenin signaling, increased Bmp2 expression, and stimulated osteoblast differentiation. Targeted deletion of the beta-catenin and Bmp2 genes abolished the stimulatory effect of Osthole on osteoblast differentiation. Since deletion of the Bmp2 gene did not affect Osthole-induced beta-catenin expression and the deletion of the beta-catenin gene inhibited Osthole-regulated Bmp2 expression in osteoblasts, we propose that Osthole acts through beta-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.
Tang
De-Zhi
DZ
Spine Research Institute, Shanghai University of Traditional Chinese Medicine, Shanghai, People's Republic of China.
Hou
Wei
W
Zhou
Quan
Q
Zhang
Minjie
M
Holz
Jonathan
J
Sheu
Tzong-Jen
TJ
Li
Tian-Fang
TF
Cheng
Shao-Dan
SD
Shi
Qi
Q
Harris
Stephen E
SE
Chen
Di
D
Wang
Yong-Jun
YJ
D000818:Animals; D001696:Biomechanical Phenomena / Q000187:drug effects; D055396:Bone Morphogenetic Protein 2 / Q000378:metabolism*; D001862:Bone Resorption / Q000473:pathology / Q000517:prevention & control; D002454:Cell Differentiation / Q000187:drug effects*; D003374:Coumarins / Q000737:chemistry / Q000494:pharmacology*; D005260:Female; D051379:Mice; D010006:Osteoblasts / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D010012:Osteogenesis / Q000187:drug effects*; D010052:Ovariectomy; D051381:Rats; D015398:Signal Transduction / Q000187:drug effects*; D051153:Wnt Proteins / Q000378:metabolism; D051176:beta Catenin / Q000378:metabolism*
D055396:Bone Morphogenetic Protein 2; D003374:Coumarins; D051153:Wnt Proteins; D051176:beta Catenin; C046627:osthol