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研究生:鍾悅華
研究生(外文):Yueh-hua Chung
論文名稱:BMP-2透過減緩TGF-β1訊息傳遞來復原肝纖維化損傷
論文名稱(外文):BMP-2 Restoration Rescues Liver Fibrosis Injuries by Attenuating TGF-β1 Signaling
指導教授:戴明泓
指導教授(外文):Ming-Hong Tai
學位類別:博士
校院名稱:國立中山大學
系所名稱:生物醫學研究所
學門:生命科學學門
學類:生物化學學類
論文種類:學術論文
論文出版年:2018
畢業學年度:106
語文別:英文
論文頁數:65
中文關鍵詞:骨形成蛋白-2上皮 - 間質轉化肝星狀細胞肝纖維化轉化生長因子-1
外文關鍵詞:Transforming growth factor-β1Hepatic fibrogenesisHepatic stellate cellsBone morphogenetic protein-2Epithelial-to-mesenchymal transition
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目的:轉化生長因子-(TGF-)在肝纖維化中扮演了重要的角色。本研究探討骨形態發生蛋白-2(BMP-2)調控肝纖維化的作用及機制。方法:我們利用肝纖維化的人體組織微陣列分析(TMA)與接受膽管結紮(BDL)手術或四氯化碳(CCl4)給藥誘導肝纖維化的小鼠模型中觀測BMP-2的表現。我們進一步使用腺病毒介導的BMP-2基因遞送來測試對肝纖維化的預防效果。小鼠的初代肝星狀細胞(pHSC)、細胞株HSC-T6肝星狀細胞和Clone 9肝臟細胞,則用來研究BMP-2和TGF-1之間的相互作用。結果:BMP-2在人類肝纖維化組織和動物肝纖維化模式中的表現顯著降低,並與肝臟TGF-1表現量呈負相關。 BMP-2基因傳遞緩解了動物肝纖維化模式中的血清中肝臟相關指數的升高,HSC活化和肝纖維化的相關標誌物。此外,外加TGF-1可根據劑量依序抑制BMP-2的表現。反之,BMP-2治療顯著抑制TGF-1及其I型和II型訊息傳遞受體的表現達,以及pHSC中誘導的Smad3磷酸化。BMP-2治療除抑制其對細胞增殖和轉移的作用外,BMP-2治療也顯著減弱了因TGF-1刺激所造成的-平滑肌肌動蛋白和纖維蛋白的高度表現,並逆轉小鼠肝臟星狀細胞中因T GF-1刺激所造成的上皮 - 間質轉換。結論:綜合我們觀察的結果,BMP-2明顯的表現出其對於肝纖維化的保護與抑制效果,而BMP-2與TGF-1之間的相互調控可能是BMP-2潛在作為在肝纖維化機轉中的抗纖維化機制。 因此,BMP-2可能可以作為治療肝纖維化的新型治療標的。
Objective: Transforming growth factor-β (TGF-β) plays a central role in hepatic fibrogenesis. This study investigated the function and mechanism of bone morphogenetic protein-2 (BMP-2) in regulation of hepatic fibrogenesis. Methods: BMP-2 expression in fibrotic liver was measured in human tissue microarray and mouse models of liver fibrosis induced by bile duct ligation (BDL) surgery or carbon tetrachloride (CCl4) administration. Adenovirus-mediated BMP-2 gene delivery was used to test the prophylactic effect on liver fibrosis. Primary hepatic stellate cells (HSC) and cell lines, HSC-T6 cells and Clone 9, were used to study the interplay between BMP-2 and TGF-β1. Results: Hepatic BMP-2 expression was significantly decreased in either human fibrotic tissues or mice fibrosis models, with a negative correlation with hepatic TGF-β1 contents. BMP-2 gene delivery alleviated the elevations of serum hepatic enzymes, HSC activation markers, and liver fibrosis in both models. Mechanistically, exogenous TGF-β1 dose-dependently reduced BMP-2 expression, whereas BMP-2 significantly suppressed expression of TGF-β and its cognate type I and II receptor peptides, as well as the induced Smad3 phosphorylation levels in primary mouse HSCs. Aside from its suppressive effects on cell proliferation and migration, BMP-2 treatment prominently attenuated the TGF-β1-stimulated α-smooth muscle actin and fibronectin expression, and reversed the TGF-β1-modulated epithelial-to-mesenchymal transition marker expression in mouse HSCs. Conclusions: The mutual regulation between BMP-2 and TGF-β1 signaling axes may constitute the anti-fibrogenic mechanism of BMP-2 in the pathogenesis of liver fibrosis. BMP-2 may potentially serve as a novel therapeutic target for treatment of liver fibrosis.
書名頁……………..………………………………………………….. i
論文審定書………..……………… ………………………………….. ii
論文公開授權書……………………………………………………… iii
誌謝………………………………………………………………….… iv
中文摘要………………………………………………………….….. v
英文摘要………………………………………..……………………. vi
目錄………………………………………..…………………….……. vii
縮寫表………………………………………..……………………..… viii
圖次………………………………………..……………………..…… ix
論文正文………………………………………………………..……… x
參考文獻……………………………………………………….…… 19
附錄……………………………………………………………………. 52
1.Lee UE, Friedman SL. Mechanisms of hepatic fibrogenesis. Best Pract Res Clin Gastroenterol 2011;25:195-206.
2.Friedman SL. Evolving challenges in hepatic fibrosis. Nat Rev Gastroenterol Hepatol 2010;7:425-436.
3.Bataller R, Brenner DA. Liver fibrosis. J Clin Invest 2005;115:209-218.
4.Hamada T, Fondevila C, Busuttil RW, Coito AJ. Metalloproteinase-9 deficiency protects against hepatic ischemia/reperfusion injury. Hepatology 2008;47:186-198.
5.Periasamy S, Hsu DZ, Chen SY, Yang SS, Chandrasekaran VR, Liu MY. Therapeutic sesamol attenuates monocrotaline-induced sinusoidal obstruction syndrome in rats by inhibiting matrix metalloproteinase-9. Cell Biochem Biophys 2011;61:327-336.
6.McGuire RF, Bissell DM, Boyles J, Roll FJ. Role of extracellular matrix in regulating fenestrations of sinusoidal endothelial cells isolated from normal rat liver. Hepatology 1992;15:989-997.
7.Bissell DM, Roulot D, George J. Transforming growth factor beta and the liver. Hepatology 2001;34:859-867.
8.Jonsson JR, Clouston AD, Ando Y, Kelemen LI, Horn MJ, Adamson MD, Purdie DM, et al. Angiotensin-converting enzyme inhibition attenuates the progression of rat hepatic fibrosis. Gastroenterology 2001;121:148-155.
9.Verrecchia F, Chu ML, Mauviel A. Identification of novel TGF-beta /Smad gene targets in dermal fibroblasts using a combined cDNA microarray/promoter transactivation approach. J Biol Chem 2001;276:17058-17062.
10.Ogawa K, Chen F, Kuang C, Chen Y. Suppression of matrix metalloproteinase-9 transcription by transforming growth factor-beta is mediated by a nuclear factor-kappaB site. Biochem J 2004;381:413-422.
11.Duarte S, Baber J, Fujii T, Coito AJ. Matrix metalloproteinases in liver injury, repair and fibrosis. Matrix Biol 2015;44-46:147-156.
12.Choi YA, Kang SS, Jin EJ. BMP-2 treatment of C3H10T1/2 mesenchymal cells blocks MMP-9 activity during chondrocyte commitment. Cell Biol Int 2009;33:887-892.
13.Alcolado R, Arthur MJ, Iredale JP. Pathogenesis of liver fibrosis. Clin Sci (Lond) 1997;92:103-112.
14.Friedman SL. Molecular mechanisms of hepatic fibrosis and principles of therapy. J Gastroenterol 1997;32:424-430.
15.Nguyen-Lefebvre AT, Horuzsko A. Kupffer Cell Metabolism and Function. J Enzymol Metab 2015;1.
16.Liu X, Hu H, Yin JQ. Therapeutic strategies against TGF-beta signaling pathway in hepatic fibrosis. Liver Int 2006;26:8-22.
17.Border WA, Noble NA. Transforming growth factor beta in tissue fibrosis. N Engl J Med 1994;331:1286-1292.
18.Wozney JM, Rosen V, Celeste AJ, Mitsock LM, Whitters MJ, Kriz RW, Hewick RM, et al. Novel regulators of bone formation: molecular clones and activities. Science 1988;242:1528-1534.
19.Massague J. The transforming growth factor-beta family. Annu Rev Cell Biol 1990;6:597-641.
20.Rossi JM, Dunn NR, Hogan BL, Zaret KS. Distinct mesodermal signals, including BMPs from the septum transversum mesenchyme, are required in combination for hepatogenesis from the endoderm. Genes Dev 2001;15:1998-2009.
21.Aykul S, Martinez-Hackert E. Transforming Growth Factor-beta Family Ligands Can Function as Antagonists by Competing for Type II Receptor Binding. J Biol Chem 2016;291:10792-10804.
22.Itoh S, Itoh F, Goumans MJ, Ten Dijke P. Signaling of transforming growth factor-beta family members through Smad proteins. Eur J Biochem 2000;267:6954-6967.
23.Feng XH, Derynck R. Specificity and versatility in tgf-beta signaling through Smads. Annu Rev Cell Dev Biol 2005;21:659-693.
24.Eickelberg O, Morty RE. Transforming growth factor beta/bone morphogenic protein signaling in pulmonary arterial hypertension: remodeling revisited. Trends Cardiovasc Med 2007;17:263-269.
25.Song JJ, Celeste AJ, Kong FM, Jirtle RL, Rosen V, Thies RS. Bone morphogenetic protein-9 binds to liver cells and stimulates proliferation. Endocrinology 1995;136:4293-4297.
26.Duncan SA, Watt AJ. BMPs on the road to hepatogenesis. Genes Dev 2001;15:1879-1884.
27.Yang YL, Liu YS, Chuang LY, Guh JY, Lee TC, Liao TN, Hung MY, et al. Bone morphogenetic protein-2 antagonizes renal interstitial fibrosis by promoting catabolism of type I transforming growth factor-beta receptors. Endocrinology 2009;150:727-740.
28.Yang YL, Ju HZ, Liu SF, Lee TC, Shih YW, Chuang LY, Guh JY, et al. BMP-2 suppresses renal interstitial fibrosis by regulating epithelial-mesenchymal transition. J Cell Biochem 2011;112:2558-2565.
29.Shlyonsky V, Soussia IB, Naeije R, Mies F. Opposing effects of bone morphogenetic protein-2 and endothelin-1 on lung fibroblast chloride currents. Am J Respir Cell Mol Biol 2011;45:1154-1160.
30.Boltjes A, Movita D, Boonstra A, Woltman AM. The role of Kupffer cells in hepatitis B and hepatitis C virus infections. J Hepatol 2014;61:660-671.
31.Kao YH, Chen CL, Jawan B, Chung YH, Sun CK, Kuo SM, Hu TH, et al. Upregulation of hepatoma-derived growth factor is involved in murine hepatic fibrogenesis. J Hepatol 2010;52:96-105.
32.Tai MH, Cheng H, Wu JP, Liu YL, Lin PR, Kuo JS, Tseng CJ, et al. Gene transfer of glial cell line-derived neurotrophic factor promotes functional recovery following spinal cord contusion. Exp Neurol 2003;183:508-515.
33.Huang YH, Tiao MM, Huang LT, Chuang JH, Kuo KC, Yang YL, Wang FS. Activation of Mir-29a in Activated Hepatic Stellate Cells Modulates Its Profibrogenic Phenotype through Inhibition of Histone Deacetylases 4. PLoS One 2015;10:e0136453.
34.Kao YH, Chen PH, Wu TY, Lin YC, Tsai MS, Lee PH, Tai TS, et al. Lipopolysaccharides induce Smad2 phosphorylation through PI3K/Akt and MAPK cascades in HSC-T6 hepatic stellate cells. Life Sci 2017;184:37-46.
35.Nakatsuka R, Taniguchi M, Hirata M, Shiota G, Sato K. Transient expression of bone morphogenic protein-2 in acute liver injury by carbon tetrachloride. J Biochem 2007;141:113-119.
36.Cai J, Zhao Y, Liu Y, Ye F, Song Z, Qin H, Meng S, et al. Directed differentiation of human embryonic stem cells into functional hepatic cells. Hepatology 2007;45:1229-1239.
37.Gressner AM. Cytokines and cellular crosstalk involved in the activation of fat-storing cells. J Hepatol 1995;22:28-36.
38.Zhang QD, Xu MY, Cai XB, Qu Y, Li ZH, Lu LG. Myofibroblastic transformation of rat hepatic stellate cells: the role of Notch signaling and epithelial-mesenchymal transition regulation. Eur Rev Med Pharmacol Sci 2015;19:4130-4138.
39.Gao X, Cao Y, Yang W, Duan C, Aronson JF, Rastellini C, Chao C, et al. BMP2 inhibits TGF-beta-induced pancreatic stellate cell activation and extracellular matrix formation. Am J Physiol Gastrointest Liver Physiol 2013;304:G804-813.
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