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Diosgenin Induces Hypoxia-Inducible Factor-1 Activation and Angiogenesis through Estrogen Receptor-Related Phosphatidylinositol 3-kinase/Akt and p38 Mitogen-Activated Protein Kinase Pathways in Osteoblasts

Departments of Primary Care Medicine (M.L.Y.), Obstetrics & Gynecology (M.L.Y.), and Traumatology & Surgery (C.Y.Y.), National Taiwan University Hospital, Taipei, Taiwan; and Institute of Toxicology (J.L.S., C.Y.Y., W.F.C., C.C.C., M.L.K.) and Department of Anatomy and Cell Biology (C.L.C., K.W.T.), College of Medicine, National Taiwan University, Taipei, Taiwan

Diosgenin, extracted from the root of wild yam (Dioscorea villosa), has been reported to demonstrate an opportunity for medical application. Vascular endothelial growth factor-A (VEGF-A) plays an important role in bone-related angiogenesis, a critical process occurring during bone formation and fracture healing. In this study, we examine whether diosgenin is able to induce VEGF-A expression and to promote angiogenesis in osteoblasts. For murine MC3T3-E1 preosteoblast-like cells, VEGF-A mRNA and protein expression seemed to be significantly elevated in response to diosgenin in a concentration-dependent fashion. Conditioned media prepared from cells treated with diosgenin induced strong angiogenic activity in either in vitro or ex vivo angiogenesis assay. Furthermore, diosgenin treatment increased the stability and activity of HIF-1 protein. Inhibition of HIF-1 activity by transfection with DN-HIF-1 significantly diminished diosgenin-mediated VEGF-A up-regulation. The use of pharmacological inhibitors or genetic inhibition revealed that both the phosphatidylinositol 3-kinase (PI3K)/Akt and p38 signaling pathways were potentially required for diosgenin-induced HIF-1 activation and subsequent VEGF-A up-regulation. It is noteworthy that an estrogen receptor binding assay revealed that diosgenin has the strong ability to replace [³H]estradiol bound to estrogen receptor (IC₅₀, 10 nM). In addition, the specific estrogen receptor antagonists ICI 182,780 (faslodex) and tamoxifen were noted to be able to strongly inhibit diosgenin-induced, src kinase-dependent Akt and p38 MAPK activation. Taken together, such results provide evidence that diosgenin up-regulates VEGF-A and promotes angiogenesis in preosteoblast-like cells by a hypoxia-inducible factor-1-dependent mechanism involving the activation of src kinase, p38 MAPK, and Akt signaling pathways via estrogen receptor.

Received for publication December 7, 2004.

Accepted for publication July 1, 2005.

Address correspondence to: Min-Liang Kuo, Laboratory of Molecular and Cellular Toxicology, Institute of Toxicology, College of Medicine, National Taiwan University, 1, Section 1, Jen-Ai Road, Taipei, Taiwan. E-mail: toxkml{at}ha.mc.ntu.edu.tw

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