探討黃酮醇類化合物對人類牙髓幹細胞骨化的不同影響及其機轉

Investigating the differential effects and the mechanisms of flavonols on bone mineralization of human dental pulp stem cells

李宜昇(Yi-Sheng Lee)

指導教授 ： 李勝揚

臺北醫學大學/口腔醫學院/牙醫學系碩博士班/碩士(2013年)

摘要

類黃酮素 (flavonoids) 是普遍存在於植物組織內的色素。部分這類化合物，尤其異黃酮，在過去被視為於更年期婦女骨質疏鬆症治療中，可取代傳統賀爾蒙替代療法的方案，而有些文獻也指出某些類黃酮素可以促進骨母細胞的骨化。人類牙髓幹細胞屬於間質幹細胞，具有自我更新以及多元分化的能力，因此在組織修復以及傷口癒合佔有很重要的角色。臨床上，各種骨頭缺損的治療，若能合併適當的類黃酮素與人類牙髓幹細胞，相信能提供骨頭癒合與再生更好的質與量，尤其在口腔齒槽骨之重建。本論文探討四種黃酮醇類化合物kaempferol、morin、quercetin、myricetin對人類牙髓幹細胞骨分化的影響，觀察因子包括鹼性磷酸酶活性、骨化相關蛋白與鈣沉積的表現、訊息傳導路徑的差異。結果發現四種黃酮醇類化合物中，kaempferol促進人類牙髓幹細胞骨化較果最好，quercetin次之，morin對人類牙髓幹細胞骨化沒有促進或抑制效果，myricetin則能抑制人類牙髓幹細胞骨化。本研究發現，黃酮醇類B環結構上的氫氧基對於人類牙髓幹細胞的骨化有決定性的影響。本文推測雌激素受體與具有特殊B環結構的 kaempferol 或 quercetin （而非morin或myricetin） 結合後，將導致下游Erk磷酸激酶的活化，最終導致骨化相關基因與蛋白質的表現。這個發現有利於未來開發新的骨癒合藥物。本研究對於臨床上以牙髓幹細胞為基礎的骨癒合療法具有重要參考價值。

關鍵字

人類牙髓幹細胞 ； 骨分化 ； 類黃酮素 ； 訊息傳導

並列摘要

Flavonoids refer to pigments that are widely distributed in plants. Some of these compounds have been considered for the treatment of osteoporosis, as an alternative to traditional hormone replacement therapy (HRT). In addition, a number of studies have shown that some flavonoids promote osteogenic differentiation of osteoblasts. Because human dental pulp stem cells (DPSCs), which are classified as mesenchymal stem cells, have self-renewal and multilineage differentiation capacities, they play a crucial role in tissue repair and wound healing. Regarding the treatment of various bone defects, a combination of suitable flavonoids and human DPSCs can enhance the quality and extent of bone defect healing and bone regeneration. This study investigated the effects of certain flavonols, namely, kaempferol, morin, quercetin, and myricetin, on the osteogenesis of human DPSCs. The parameters studied includes alkaline phosphatase (ALP) activity, osteogenesis-related protein expression, calcium deposition, and differences in signal transduction mechanisms. The results show that kaempferol achieved the greatest performance for promoting the osteogenic differentiation of human DPSCs, followed by quercetin. By contrast, morin exhibited neither promotional nor inhibitory effects, and myricetin had an inhibitory effect. This study also found that the hydroxyl moieties in the B-ring of flavonols played a crucial role in the osteogenesis of human DPSCs. We contend that the binding of estrogen receptors with the unique structural B-ring of either kaempferol or quercetin, but not morin or myricetin, induced the downstream activation of Erk and the expression of osteogenesis-related genes and proteins. This finding may benefit the future design of bone regeneration drugs. The results of this study are clinically vital for DPSC-based bone regeneration.

並列關鍵字

human dental pulp stem cell ； osteogenesis ； flavonoids ； signal transduction

參考文獻

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