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研究生:劉峰誠
研究生(外文):Feng-Cheng Liu
論文名稱:探討白藜蘆醇與小分子藥物在豬軟骨細胞中軟骨保護作用與分子機制
論文名稱(外文):Study of chondroprotection and molecular mechanisms of resveratrol and small molecules in porcine primary chondrocytes
指導教授:賴振宏賴振宏引用關係
指導教授(外文):Jenn-Haung Lai
口試委員:張德明黃旭山何令君黃怡超賴振宏
口試委員(外文):Deh-Ming ChangHsu-Shan HuangLing-Jun HoYi-Tsau HuangJenn-Haung Lai
口試日期:2011-08-17
學位類別:博士
校院名稱:國防醫學院
系所名稱:醫學科學研究所
學門:醫藥衛生學門
學類:醫學學類
論文種類:學術論文
論文出版年:2011
畢業學年度:99
語文別:中文
論文頁數:125
中文關鍵詞:退化性關節炎軟骨細胞白藜蘆醇糖化終產物干擾素調節因子1小分子藥物腫瘤壞死因子α
外文關鍵詞:osteoarthritischondrocytesresveratroladvanced glycation end productsinterferon regulatory factor-1small moleculesTumor necrosis factor-α
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簡介
在骨關節炎中糖化終產物(AGE)累積關節腔組織是造成軟骨損傷的致病因素。我們首先研究白藜蘆醇在糖化終產物刺激豬軟骨細胞與軟骨塊後,探討其軟骨保護的效果。另更進一步使用腫瘤壞死因子-α刺激豬軟骨細胞作為篩選工具,評估合成的小分子藥物對退化性關節炎的免疫調節作用。
材料和方法
關節軟骨細胞是從後腿豬關節取得並分離。白藜蘆醇購買自Sigma公司;300種苯甲醯胺小分子藥物從藥學所黃旭山所長實驗室取得。電泳遷移實驗(EMSA)、西方點墨和轉染法來評估IκB激酶(IκB kinase)-IκBα-激活核因子-κB(NF-κB)和N-末端激酶(JNK)和細胞外信號調節激酶(ERK)-激活蛋白-1(AP-1)轉錄因子的活性。誘導型一氧化氮合酶-一氧化氮和環氧合酶-2-前列腺素E2(iNOS-NO和COX-2-PGE2)的含量用西方點墨、Griess反應法或酶聯免疫吸附測定法(ELISA)來分析。即時多聚酶鏈反應法(RT/PCR)和明膠酶譜法(gelatin zymography)分別評估基質金屬蛋白酶(MMPs)和蛋白聚醣酶 (aggrecanases)的表達與活性。軟骨塊則以番紅/快速綠/蘇木等染色法來評估蛋白多醣與蛋白聚糖的降解作用。
結果
白藜蘆醇(resveratrol)在抑制糖化終產物誘導iNOS和COX-2的表達與NO和PGE2的產生上則有顯著的效果。這種影響可能是抑制IKK-IκBα-NF-κB與JNK/ERK-AP-1的訊息傳導。藉由抑制上述訊息傳導的途徑,白藜蘆醇也能降低MMP-13的活性與表達,避免糖化終產物誘導第二型膠原蛋白的降解作用。組織化學染色分析法更進一步證明白藜蘆醇能避免軟骨塊中蛋白多醣與蛋白聚糖的降解作用。另外從一系列苯甲醯胺類的新型小分子藥物篩選試驗中發現,2-羥基-N-[3-(三氟甲基)苯基]苯甲醯胺(HS-Cf)能在豬軟骨細胞試驗中,能有效的抑制TNF-α刺激所產生的NO和iNOS表達。HS-Cf也發現能抑制TNF-α誘導基質金屬蛋白酶與蛋白聚醣酶的活性,並阻止第二型膠原蛋白的減少。組織化學染色法也證實在軟骨塊的試驗中,HS-Cf可以減緩TNF-α引起蛋白多醣/蛋白聚醣的降解作用。此HS-Cf作用可能是經由抑制TNF-α誘導干擾素調節因子1(IRF-1),但不是NF-κB信息傳導。短髮夾剃除(short hairpin knock-down)的研究則進一步證實IRF-1的重要性,因此證實HS-Cf可做為新穎治療退化性關節炎的先導藥物研發。
結論
目前的研究闡明白藜蘆醇保護糖化終產物對軟骨損傷的效用與機轉,與其在治療退化性關節炎的療效。更進一步在300個的小分子藥物篩選中,我們確定了一種苯甲酰胺的小分子,2-羥基-N-[3-(三氟甲基)苯基]苯甲醯胺(HS-Cf)是經由抑制TNF-α誘導的IRF-1活化來防止軟骨的破壞。白藜蘆醇與HS-Cf可能在退化性關節炎的新藥研發上是一個極具潛力的先導候選藥物。

Introduction
Accumulation of advanced glycation end products (AGEs) in joints contributes to the pathogenesis of cartilage damage in osteoarthritis (OA). We first explore the potential chondroprotective effects of resveratrol on AGEs-stimulated porcine chondrocytes and cartilage explants. In addition, by using tumor necrosis factor-alpha (TNF-α)-activated porcine chondrocytes as a screening tool, we further studied and identified small-molecule inhibitors preserving immunomodulatory effects as therapeutics for OA.
Methods
Chondrocytes were isolated from pig joints. A minilibrary of 300 benzamide-linked small molecules was established. Activation of the IκB kinase (IKK)-IκBα-nuclear factor-kappaB (NF-κB) and c-Jun N-terminal kinase (JNK)/extracellular signal-regulated kinase (ERK)-activator protein-1 (AP-1) pathways was assessed by electrophoretic mobility shift assay (EMSA), Western blot and transfection assay. The levels of inducible nitric oxide synthase (iNOS)-NO and cyclooxygenase-2 (COX-2)-prostaglandin E2 (PGE2) were measured by Western blot, Griess reaction or ELISA. Zymography and real-time RT-PCR were used to determine enzyme activity and expression of matrix metalloproteinases (MMPs) and aggrecanases, respectively. Proteoglycan degradation in cartilage explants was determined by histochemistry analysis.
Results
We show that AGEs-induced expression of iNOS and COX-2 and production of NO and PGE2 were suppressed by resveratrol. Such effects of resveratrol were likely mediated through inhibiting IKK-IκBα-NF-κB and JNK/ERK-AP-1 signaling pathways induced by AGEs. By targeting these critical signaling pathways, resveratrol decreased AGEs-stimulated expression and activity of MMP-13 and prevented AGEs-mediated destruction of collagen II. Histochemistry analysis further confirms that resveratrol could prevent AGEs-induced degradation of proteoglycan and aggrecan in cartilage explants. Future studies on the small molecules are therefore recommended. Bioassay screening of benzamide-linked small molecules revealed that 2-hydroxy-N-[3-(trifluoromethyl)phenyl]benzamide (HS-Cf) was a potent inhibitor of NO production and iNOS expression in TNF-α-stimulated porcine chondrocytes. HS-Cf suppressed TNF-α-induced activity of MMP-13 and expressions of several aggrecanases and prevented TNF-α-mediated reduction of collagen II. Histochemistry analysis confirmed that HS-Cf could prevent TNF-α-induced degradation and release of proteoglycan/aggrecan in cartilage explants. Such effects by HS-Cf were likely through suppressing TNF-α-induced interferon regulatory factor-1 (IRF-1) but not nuclear factor kappaB (NF-κB) signaling. The significance of IRF-1 was further confirmed by short hairpin knock-down studies.
Conclusions
The present study reveals not only the effects and mechanisms regarding how resveratrol may protect cartilage from AGEs-mediated damage but also the potential therapeutic benefit of resveratrol in the treatment of OA. In a minilibrary containing 300 small molecules, we identified a benzamide-linked small molecule, 2-hydroxy-N-[3-(trifluoromethyl)phenyl]benzamide (HS-Cf), that through down-regulating TNF-α-induced IRF-1 activity suppressed chondrocyte activation and prevented cartilage destruction. Both resveratrol and HS-Cf might be a potential disease-modifying drug for OA therapeutics.

TEXT CATALOG
1. INTRODUCTION
1.1. Etiology of OA
1.1.1. Osteoarthritis and ageing
1.1.2. Advanced glycation end products (AGEs)
1.1.3. OA and inflammatory cytokines
1.2. Articular cartilage is the target tissue of OA
1.2.1. Structure and function of articular cartilage
1.2.2. Composition of articular cartilage
1.2.3. Homeostasis of articular cartilage and molecular mechanisms of tissue remodeling in the process of OA development
1.3. Current clinical treatment and its limitation
1.3.1 Resveratrol
1.3.2 Small molecules
1.4. Resveratrol and HS-Cf on OA therapy

2. MATERIALS AND MATHODS
2.1. Reagents and antibodies
2.2. Preparation of AGEs
2.3. Isolation and culture of porcine chondrocytes
2.4. Cytotoxicity analysis
2.5. Transfection and luciferase assays
2.6. Measurement of NO and PGE2 concentrations
2.7. Western blotting
2.8. Nuclear extract preparation and electrophoretic mobility shift assay
2.9. Gelatin zymography
2.10. Immunoprecipitation kinase assay
2.11. Real-time RT/PCR
2.12. Preparation of cartilage explants
2.13. Analysis of cartilage degradation
2.14. Safranin O staining and measurement of the aggrecan NITEGE neoepitope
2.15. shRNA knock-down
2.16. Statistical analysis

3. Chondroprotective effects and mechanisms of resveratrol in advanced glycation end productsstimulated chondrocytes
3.1. Resveratrol inhibited iNOS-NO and COX-2-PGE2 production in AGEs-stimulated porcine chondrocytes
3.2. Resveratrol suppressed AGEs-stimulated IKK-IκBα-NF-κB signaling
3.3. Down-regulation of AGEs-activated AP-1 signaling by resveratrol
3.4. Resveratrol affected AGEs-regulated MMP-13 expression and activity and collagen II level
3.5. Resveratrol protected against AGEs-induced proteoglycan and aggrecan degradation in cartilage explants

4. A benzamide-linked small molecule HS-Cf inhibits TNF-α-induced Interferon Regulatory Factor-1 in porcine chondrocytes: A potential disease-modifying drug for osteoarthritis therapeutics
4.1. Benzamide-linked small molecules inhibited iNOS-NO production in TNF-α-stimulated porcine chondrocytes
4.2. HS-Cf suppressed TNF-a-induced MMP-13 expression and activity as well as prevented TNF-a-mediated collagen II reduction
4.3. HS-Cf inhibited TNF-a-induced MMP-1, MMP-3, ADAMTS4 and ADAMTS5 expression
4.4. HS-Cf protected against TNF-a-induced proteoglycan/aggrecan degradation in cartilage explants
4.5. HS-Cf could not suppress TNF-a-stimulated NF-κB and AP-1 signaling pathways
4.6. HS-Cf suppressed TNF-a-stimulated IRF-1
4.7. Knock-down of IRF-1 by short hairpin RNA inhibited TNF-α-induced activation of iNOS and MMP-13

5. DISCUSSION
5.1. The drugs for choice of OA
5.2. Three major well-characterized AGEs
5.3 The physiological concentration of AGEs
5.4. COX-2 and iNOS
5.5. NF-κB and AP-1 signaling
5.6. MMP-13 expression and degradation of cartilage components
5.7. Two major limitations in the paper of resveratrol
5.8. Resveratrol could be effective for RA.
5.9. Small molecules for OA therapeutics
5.10. Therapeutic benefits of HS-Cf
5.11. HS-Cf as the potential candidate for anti-OA therapeutics
5.12. IRF-1 in TNF-α-mediated damage of cartilage
5.13. IRF-1, a specificity of HS-Cf-mediated immunomodulatory effects

6. CONCLUSION

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