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完整後設資料紀錄
DC 欄位 | 值 | 語言 |
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dc.contributor.advisor | 郭明良(Min-Liang Kuo) | |
dc.contributor.author | Jean Chiou | en |
dc.contributor.author | 邱勤 | zh_TW |
dc.date.accessioned | 2021-06-13T00:24:27Z | - |
dc.date.available | 2007-08-08 | |
dc.date.copyright | 2007-08-08 | |
dc.date.issued | 2007 | |
dc.date.submitted | 2007-07-27 | |
dc.identifier.citation | 1. Patricia Ducy, Thorsten Schinke, Gerard Karsenty. The osteoblast: A sophisticated fibroblast under central surveillance. Science 2000; 289: 1501-1504.
2. Shun-ichi Harada, Gideon A. Rodan. Control of osteoblast function and regulation of bone mass. Nature 2003; 423: 349-355. 3. Steven L. Teitelbaum, F. Patrick Ross. Genetic regulation of osteoclast development and function. Nat. Rev. Genet. 2003; 4: 638-649. 4. William J. Boyle, W. Scott Simonet, David L. Lacey. Osteoclast differentiation and activation. Nature 2003; 423: 337-342. 5. Gerard Karsenty. The complexities of skeletal biology. Nature 2003; 423: 316-318. 6. Steven L. Teitelbaum. Bone resorption by osteoclasts. Science 2000; 289: 1504-1508. 7. Gideon A. Rodan, T. John Martin. Therapeutic approaches to bone diseases. Science 2000; 289: 1508-1514. 8. Manolagas SC and Jilka RL. Bone marrow, cytokines and bone remodeling. Emerging insights into the pathophysiology of osteoporosis. N. Engl. J. Med. 1995; 332: 305-311. 9. Randell A, Sambrook PN, Nguyen TV, et al. Direct clinical and welfare costs of osteoporotic fractures in elderly men and women. Osteoporosis Int. 1995; 5: 427-432. 10. Sanders KM, Nicholson GC, Ugoni AM, et al. Health burden of hip and other fractures in Australia beyond 2000 projections based on the Geelong osteoporosis study. Med. J. Aust. 1999; 170: 467-470. 11. Center JR, Nguyen TV, Schneider D, et al. Mortality after all major types of osteoporotic fracture in men and women: an observation study. Lancet 1999; 353: 878-882. 12. Brigstock DR. The connective tissue growth factor/cysteine-rich 61/nephroblastoma overexpressed (CCN) family. Endocr Rev. 1999; 20(2):189-206. 13. Yan X, Baxter RC, Perbal B, Firth SM. The aminoterminal insulin-like growth factor (IGF) binding domain of IGF binding protein-3 cannot be functionally substituted by the structurally homologous domain of CCN3. Endocrinology. 2006; 147(11):5268-74. 14. Chaqour B, Goppelt-Struebe M. Mechanical regulation of the Cyr61/CCN1 and CTGF/CCN2 proteins. FEBS J. 2006; 273(16):3639-49. 15. Desnoyers L. Structural basis and therapeutic implication of the interaction of CCN proteins with glycoconjugates. Curr Pharm Des. 2004;10(31):3913-28 16. Perbal B. CCN proteins: multifunctional signalling regulators. Lancet. 2004; 363(9402):62-4 17. Lin MT, Chang CC, Chen ST, Chang HL, Su JL, Chau YP, Kuo ML. Cyr61 expression confers resistance to apoptosis in breast cancer MCF-7 cells by a mechanism of NF-kappaB-dependent XIAP up-regulation. J Biol Chem. 2004; 279(23):24015-23 18. Croci S, Landuzzi L, Astolfi A, Nicoletti G, Rosolen A, Sartori F, Follo MY, Oliver N, De Giovanni C, Nanni P, Lollini PL. Inhibition of connective tissue growth factor (CTGF/CCN2) expression decreases the survival and myogenic differentiation of human rhabdomyosarcoma cells. Cancer Res. 2004; 64(5):1730-6. 19. Menendez JA, Mehmi I, Griggs DW, Lupu R. The angiogenic factor CYR61 in breast cancer: molecular pathology and therapeutic perspectives. Endocr Relat Cancer. 2003; 10(2):141-52 20. Leng E, Malcolm T, Tai G, Estable M, Sadowski I. Organization and expression of the Cyr61 gene in normal human fibroblasts. J Biomed Sci. 2002; 9(1):59-67. 21. French DM, Kaul RJ, D'Souza AL, Crowley CW, Bao M, Frantz GD, Filvaroff EH, Desnoyers L. WISP-1 is an osteoblastic regulator expressed during skeletal development and fracture repair. Am J Pathol. 2004; 165(3):855-67 22. Babic AM, Chen CC, Lau LF. Fisp12/mouse connective tissue growth factor mediates endothelial cell adhesion and migration through integrin alphavbeta3, promotes endothelial cell survival, and induces angiogenesis in vivo. Mol Cell Biol. 1999; 19(4):2958-66 23. Hirasaki S, Koide N, Ujike K, Shinji T, Tsuji T. Expression of Nov, CYR61 and CTGF genes in human hepatocellular carcinoma. Hepatol Res. 2001; 19(3):294-305 24. Wong M, Kireeva ML, Kolesnikova TV, Lau LF. Cyr61, product of a growth factor-inducible immediate-early gene, regulates chondrogenesis in mouse limb bud mesenchymal cells. Dev Biol. 1997; 192(2):492-508 25. Hadjiargyrou M, Ahrens W, Rubin CT. Temporal expression of the chondrogenic and angiogenic growth factor CYR61 during fracture repair. J Bone Miner Res. 2000; 15(6):1014-23. 26. O'Brien TP, Lau LF. Expression of the growth factor-inducible immediate early gene cyr61 correlates with chondrogenesis during mouse embryonic development. Cell Growth Differ. 1992; 3(9):645-54. 27. Parisi MS, Gazzerro E, Rydziel S, Canalis E. Expression and regulation of CCN genes in murine osteoblasts. Bone. 2006; 38(5):671-7. 28. Schutze N, Lechner A, Groll C, Siggelkow H, Hufner M, Kohrle J, Jakob F. The human analog of murine cystein rich protein 61 [correction of 16] is a 1alpha,25-dihydroxyvitamin D3 responsive immediate early gene in human fetal osteoblasts: regulation by cytokines, growth factors, and serum. Endocrinology. 1998; 139(4):1761-70. 29. Si W, Kang Q, Luu HH, Park JK, Luo Q, Song WX, Jiang W, Luo X, Li X, Yin H, Montag AG, Haydon RC, He TC. CCN1/Cyr61 is regulated by the canonical Wnt signal and plays an important role in Wnt3A-induced osteoblast differentiation of mesenchymal stem cells. Mol Cell Biol. 2006; 26(8):2955-64. 30. Marshall R. Urist . Bone formation by autoinduction, Science (1965); 150: 893-899 31. Sykaras N. and Opperman LA. Bone morphogenetic proteins (BMPs): how do they function and what can they offer the clinician? J. Oral. Sci. 2003; 45: 57-73. 32. Nohe A., Keating E., Knaus P., Petersen NO. Signal transduction of bone morphogenetic protein receptors. Cell Signal 2004; 16: 291-299. 33. Xiao Y., Haase H., Young WG, Bartold PM. Development and transplantation of a mineralized matrix formed by osteoblasts in vitro for bone regeneration. Cell Transplant. 2004: 13:15-25. 34. Riko Nishimura, Yoichi Kato, Di Chen, Stephen E. Harris, Gregory R. Mundy, and Toshiyuki Yoneda. Smad5 and DPC4 are key molecules in mediating BMP-2-induced osteoblastic differentiation of the pluripotent mesenchymal precursor cell line C2C12. J. Biol. Chem.1998; 273: 1872-1879 35. K. Yagi , K. Tsuji , A. Nifuji , K. Shinomiya , K. Nakashima , B. deCrombrugghe , Masaki Noda. Bone morphogenetic protein-2 enhances osterix gene expression in chondrocytes. J Cell Biochem. 2003 Apr 15;88(6):1077-83. 36. Di Chen, Ming Zhao, Gregory R. Mundy. Bone morphogenetic proteins. Growth Factors. 2004; 22(4): 233-241. 37. Norbert Shütze, Karin Kunzi-Rapp, Rita Wagemanns, Ulrich Nöth, Susanne Jauzke, Franz Jakob. Expression, purification, and functional testing of recombinant CYR61/CCN1. Protein Expr Purif. 2005; 42(1): 219-225. 38. A. Lechner, N. Shütze, H. Siggelkow, J. Seufert, F. Jakob. The immediate early gene product hCYR61 localizes to the secretory pathway in human osteoblasts. Bone. 2000; 27(1): 53-60. 39. Jaiswal RK, Jaiswal N, Bruder SP, Mbalaviele G, Marshak DR, Pittenger MF. Adult human mesenchymal stem cell differentiation to the osteogenic or adipogenic lineage is regulated by mitogen-activated protein kinase. J. Biol. Chem. 2000; 275: 9645-9652. 40. Rodriguez JP, Rios S, Fernandez M, Santibanez JF. Differential activation of ERK1/2 MAP kinase signaling pathway in mesenchymal stem cell from control and osteoporotic postmenopausal women. J. Cell Biochem. 2004; 291:201-211. 41. Cortizo AM, Lettieri MG, Barrio DA, Mercer N, Etcheverry SB, McCarthy AD. Advanced glycation end-products (AGEs) induce concerted changes in the osteoblastic expression of their receptor RAGE and in the activation of extracellular signal-regulated kinases (ERK). Mol. Cell Biochem. 2003; 250:1-10. 42. Shin-jiro Kono, Yasushi Oshima, Kazuto Hoshi, Lynda F. Bonewald, Hiromi Oda, Kozo Nakamura, Hiroshi Kawaguchi, Sakae Tanaka. Erk pathways negatively regulate matrix mineralization. Bone 2007; 40(1): 68-74. 43. Kireeva, M. L., Lam, S. C-T., Lau, L. F. Adhesion of human umbilical vein endothelial cells to the immediate early gene product cyr61 is mediated through integrin alphavbeta3. J. Biol. Chem. 1998; 273: 3090-3096. 44. Ying Chen, Xiao-Yan Du. Functional properties and intracellular signaling of CCN1/Cyr61. J. Cell. Biochem. 2006; 100(6): 1337-1345. 45. Tokutaro Minamizato, Kei Sakamoto, Tingjiao Liu, Hiroki Kokubo, Ken-ichi Katsube, Bernard Perbal, Seiji Nakamura, Akira Yamaguchi. CCN3/NOV inhibits BMP-2-induced osteoblast differentiation by interacting with BMP and Notch signaling pathways. Biochem. Biophys. Res. Commun. 2007; 354:567-573. | |
dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/28822 | - |
dc.description.abstract | Cysteine rich protein 61 (CYR61) 為CCN蛋白家族的一員,是一種生長因子,此一生長因子在文獻報導中,有調控細胞發育 (development) 、增生 (proliferation) 、移行 (migration) 及分化 (differentiation)的功能。過去的文獻指出,CYR61在間質幹細胞 (mesenchymal stem cell) 分化成骨骼時會被調控而減少,但是在骨折修復時則會大量表現,顯示其在骨骼發育中之重要性。
骨質代謝包括了骨合成 (bone formation) 與骨消溶 (bone resorption) 。調控骨再塑 (bone remodeling) 的兩種主要細胞為: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可能造成病變,例如骨質疏鬆症 (osteoporosis) 或骨質石化症 (osteopetrosis) 。在骨頭受損斷裂需要癒合時,造骨細胞會移動到傷處進行分化造骨的動作。據報告指出,骨形成蛋白-2 (bone morphogenetic proteins) 可以促進間質幹細胞往硬骨方向分化,促進骨質增生,並且在造骨細胞的移行中扮演重要的角色。另有報告指出,CYR61會透過Wnt signaling pathway 調控bone formation,但BMP-2及CYR61兩者之間的訊息傳遞路徑還有待繼續研究。 因此,本實驗乃以CYR61重組蛋白處理小鼠造骨細胞 (MC3T3-E1),研究CYR61對造骨細胞分化中所扮演的角色。實驗結果發現,將CYR61重組蛋白處理造骨細胞,觀察到隨著CYR61處理濃度增加,可以促進造骨細胞的增生、移動;隨著處理時間的延長可以促使細胞礦物質化(mineralization)。RT-PCR及Western blot分析,可以觀察到bone morphogenetic protein-2 (bmp-2) 的mRNA以及蛋白質表現隨著rCYR61處理時間增加而漸增,利用BMP-2的中和抗體處理細胞再加入CYR61重組蛋白,發現細胞的增生 (proliferation)、移行(migration) 、分化 (differentiation) 的行為有隨著抗體濃度增加而有被抑制的現象。此外在訊息傳遞的探討中,我們發現CYR61重組蛋白可以活化ERK的訊息傳遞路徑,而化學抑制劑 (U0126及PD98059) 則可抑制CYR61誘發之BMP-2表現。此外,integrin alphavbeta3中和抗體可以顯著抑制ERK以及BMP-2的活化表現,甚至可抑制CYR61誘發細胞增生、移行、及分化的行為。綜合以上實驗結果,CYR61可透過integrin alphavbeta3再經由活化ERK訊息傳遞路徑來刺激細胞BMP-2基因表現,並促使造骨細胞分化。 | zh_TW |
dc.description.abstract | Bone metabolism includes bone formation and reabsoption, which is executed and regulated by osteoblasts and osteoclasts. The dysregulation of these two types of cells would cause bone disorders. When healing, osteoblast migrates to the injury site and proceeds with differentiation process. According to the previous studies, bone morphogenetic protein-2 (BMP-2) may promote mesenchymal stem cells differentiated into bony structure. Cysteine rich protein (CYR61), a member of CCN family, regulates cell development, proliferation, migration, and differentiation. It’s been shown that CYR61 plays an important role in bone development and healing, and CYR61 is regulated by Wnt3A and promotes osteoblasts differentiation. While Wnt signaling pathway is crucial for BMP-2 to induce new bone formation, the regulation mechanism between CYR61 and BMP-2 in bone formation and differentiation is still unclear.
Our current data showed that CYR61 significantly increased osteoblasts proliferation and migration in a dose-dependent manner, and increased mineralization in 14 days after treatment. Mechanistically, CYR61 enhanced bmp-2 mRNA and protein expression in time- and dose-dependent manners, and osteoblast migration, proliferation, and differentiation abilities were significantly inhibited by BMP-2 neutralizing antibody. Furthermore, we found that CYR61 induced BMP-2 expression through MAPK/Erk signal pathway. The use of pharmacological inhibitors revealed that ERK was involved in CYR61-mediated BMP-2 expression. Besides, we also showed that integrin alphavbeta3 neutralizing antibody could inhibit CYR61 activated ERK phosphorylation, BMP-2 protein expression, and osteoblast proliferation, migration, and differentiation. Taken together, our results provide evidence that rCYR61 up-regulates BMP-2 mRNA and protein expression, and promoted proliferation, migration, and differentiation through activation of ERK signaling pathway by binding to integrin alphavbeta3 receptor in preosteoblast-like cells. | en |
dc.description.provenance | Made available in DSpace on 2021-06-13T00:24:27Z (GMT). No. of bitstreams: 1 ntu-96-R94447001-1.pdf: 2688727 bytes, checksum: 35f1e95cbf6f3b1acb3f4ec0582585ba (MD5) Previous issue date: 2007 | en |
dc.description.tableofcontents | Abstract……………………………….………….………………………1-2
中文摘要…………………………………………………………………3-4 Introduction……………………………………………………………. 5-15 Specific aim……………………………………………………………….16 Materials and methods……………………………………………...…17-22 Results…………………………………………………………………23-27 Discussion……………………………………………………………..28-31 Figures and legends……………………………………………………32-47 References……………………………………………………………..48-54 | |
dc.language.iso | en | |
dc.title | CYR61 調控骨型蛋白-2 (BMP-2) 致小鼠造骨細胞分化之探討 | zh_TW |
dc.title | Cysteine Rich Protein 61 Regulates Bone Morphogenetic Protein-2-dependent Differentiation in Murine Osteoblasts | en |
dc.type | Thesis | |
dc.date.schoolyear | 95-2 | |
dc.description.degree | 碩士 | |
dc.contributor.oralexamcommittee | 嚴孟祿,莊雙恩 | |
dc.subject.keyword | 造骨細胞,分化, | zh_TW |
dc.subject.keyword | CYR61,BMP-2,osteoblast,differentiation, | en |
dc.relation.page | 54 | |
dc.rights.note | 有償授權 | |
dc.date.accepted | 2007-07-27 | |
dc.contributor.author-college | 醫學院 | zh_TW |
dc.contributor.author-dept | 毒理學研究所 | zh_TW |
顯示於系所單位: | 毒理學研究所 |
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