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標題: | SIRT6可藉由抑制過氧化物及醣解作用減緩成骨細胞低氧所誘導的發炎反應: 發炎性骨吸收的治療應用 Sirtuin 6 suppresses hypoxia-induced inflammatory response in human osteoblasts via inhibition of reactive oxygen species production and glycolysis - A therapeutic implication in inflammatory bone resorption |
作者: | Kuo-Liang Hou 侯國亮 |
指導教授: | 林思洸(Sze-Kwan Lin) |
關鍵字: | Sirtuin 6,發炎反應,過氧化物,醣解作用,骨吸收, Sirtuin 6,Inflammation,Reactive oxygen species,Glycolysis,Bone resorption, |
出版年 : | 2016 |
學位: | 博士 |
摘要: | 低氧誘導的醣解作用及氧化還原訊息傳遞在發炎性骨吸收的相關機制還不清楚。過往的文獻指出SIRT6在葡萄糖代謝及氧化還原訊息傳遞扮演重要的腳色。本篇研究中我們探討在人類成骨細胞(human osteoblast)中醣解作用和過氧化物(reactive oxygen species,ROS)生成之間的關聯性,並研究SIRT6是否會透過調節這些途徑來影響發炎反應。人類成骨細胞在低氧環境下,我們測量乳酸脫氫酶(lactate dehydrogenase A, LDHA)、乳酸及過氧化物的產生,並探討乳酸及過氧化物之間的相互關係,了解這兩個機制對於誘導發炎因子的影響。透過成骨細胞過量表現SIRT6的方式了解SIRT6是如何影響過氧化物生成及糖解作用。在大鼠關節炎模式中,我們利用lentivirus基因治療的方式將SIRT6基因或empty vector表現在關節中,利用免疫組織染色測量成骨細胞LDHA、Cyr61及巨噬細胞的吸引在發炎程度中的相關性。我們的結果顯示低氧會促進LDHA蛋白的表現和過氧化物的生成,兩者之間利用正回饋的方式相互活化。另外低氧會促進發炎因子Cyr61、TNF-α、IL-1β和IL-6的表現,並且這個現象會透過SIRT6調控醣解作用和過氧化物的生成所抑制。在關節炎動物模式中,利用基因治療的方式將SIRT6過量表現於關節時,可以減緩發炎反應、骨細胞合成Cyr61及巨噬細胞的吸引,同時也會降低LDHA及氧化性病灶組織的量。我們的結果顯示出SIRT6可藉由調控葡萄糖代謝及氧化還原平衡來減緩成骨細胞的發炎反應。在未來藉由調控代謝重組的機制,可能成為治療發炎性骨吸收的一個治療策略。 Relation between hypoxia-enhanced glycolysis and redox signaling in inflammatory bone diseases is unclear. Sirtuin 6 (SIRT6) is pivotal for glucose metabolism and redox homeostasis. In the study we examined the connection between glycolysis and reactive oxygen species (ROS) production in human osteoblasts (HOB) and assessed whether SIRT6 modulates inflammation via regulation of these activities. In HOB cultured under hypoxia, expression of lactate dehydrogenase A (LDHA), lactate production and ROS generation were examined. The reciprocal effects between lactate and ROS production and their impact on inflammatory cytokine induction were assessed. The action of SIRT6 on the above reactions was determined. In a rat model of collagen-induced arthritis (CIA), the relation between inflammatory activity and osteoblastic expression of LDHA, oxidative lesions, Cyr61 synthesis and macrophage recruitment were evaluated in joints with or without lentiviral-SIRT6 gene therapy. Results showed that hypoxia enhanced lactate and LDHA production in HOB. ROS generation also increased and there was a positive feedback between glycolysis and ROS formation. Overexpression of SIRT6 attenuated hypoxia-enhanced glycolysis and ROS generation. Hypoxia-induced expressions of Cyr61, TNF-α, IL-1β and IL-6 were suppressed by SIRT6 and the inhibitory effects overlapped with anti-glycolytic and anti-oxidation mechanisms. In CIA, overexpression of SIRT6 ameliorated inflammation, osteoblastic synthesis of Cyr61 and macrophage recruitment. Expression of LDHA and oxidative lesions were decreased in osteoblasts of SIRT6-treated joints. Our findings suggest that SIRT6 suppresses inflammatory response in osteoblasts via modulation of glucose metabolism and redox homeostasis. Reprogramming cellular metabolism may possess therapeutic potential for inflammatory bone resorption. |
URI: | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/60103 |
DOI: | 10.6342/NTU201603843 |
全文授權: | 有償授權 |
顯示於系所單位: | 臨床牙醫學研究所 |
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