薯蕷皂甘元Diosgenin促進造骨細胞產生血管內皮生長因子(VEGF-A)之機制

Diosgenin為山藥中具生理效應的主要成分，結構與固醇類荷爾蒙相似，所以廣被製藥業拿來作為合成荷爾蒙(如黃體素、睪固酮等)或類固醇製劑的原料。現已有文獻指出diosgenin可顯著減少因卵巢切除而造成骨質疏鬆老鼠之骨質流失。骨質代謝包括骨合成（bone formation）與骨吸收（bone resorption）。調控骨再塑（bone remodling）的二個主要細胞為：造骨細胞(osteoblasts) 及破骨細胞(osteoclasts)，造骨細胞主要負責骨骼的製造，破骨細胞則負責骨質的分解及再吸收的作用。當任何一種細胞太多或太少而造成體內不平衡時就有可能造成病變，例如osteoporosis (骨質疏鬆症)或osteopetrosis (骨質石化症)。正常骨頭再生及修復時需要新生血管之參與。據報導，纖維母細胞生長因子-2（fibroblast growth factor-2）、血管內皮生長因子(vascular endothelial growth factor, VEGF)以及乙型轉型生長因子(transforming growth factor-

關鍵字

血管新生；血管內皮生長因子；骨質疏鬆；薯蕷皂甘元

並列摘要

Diosgenin, a steroidal saponin that is extracted from the root of Wild Yam (Dioscorea villosa), has been reported to have tremendous medical applications. Angiogenesis is a critical process during bone formation and fracture healing and vascular endothelial growth factor-A (VEGF-A) is an important angiogenic factor produced in a regulate manner by many cell types, including osteoblasts. The aim of the present study was to examine whether diosgenin modulates VEGF-A expression in osteoblasts and promote angiogenesis. In murine MC3T3-E1 preosteoblast-like cells, we found that VEGF-A expression was significantly elevated in response to diosgenin. Conditioned media of MC3T3-E1 cells treated with diosgenin also induced a strong angiogenic activity in either in vitro nor ex vivo assay, which were blocked by VEGF-A specific neutralizing antibody. At the mechanistic level, we found that diosgenin treatment activated the Akt and p38 MAPK. The use of pharmacological inhibitors or genetic inhibition by transfection with the dominant-negative (DN)-Akt or DN-p38 plasmids revealed that both Akt and p38 MAPK signaling are involved in diosgenin-mediated VEGF-A up-regulation. Furthermore, we found that diosgenin-treated MC3T3-E1 cells showed an increased HIF-1a protein in the nucleus. Blockage of HIF-1a activity by transfection with a DN-HIF-1aexpression vector significantly abolished diosgenin-induced VEGF-A up-regulation, suggesting that diosgenin-induced VEGF-A expression was a HIF-1?dependent manner. Besides, we used a highly specific estrogen receptor antagonist ICI 182,780 to treat MC3T3-E1 cells. ICI 182,780 could inhibit diosgenin activated Akt, p38 MAPK phosphorylation and HIF-1a, VEGF-A protein expression. Taken together, our results provided evidence that diosgenin up-regulated VEGF-A and promote angiogenesis in preosteoblast-like cells by a HIF-1?dependent mechanism involving the activation of Akt and p38 MAPK signaling pathways via estrogen receptor.

並列關鍵字

Diosgenin ； Angiogenesis ； Vascular Endothelial Growth Factor-A ； Osteoporosis

參考文獻

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薯蕷皂甘元Diosgenin促進造骨細胞產生血管內皮生長因子(VEGF-A)之機制

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