請用此 Handle URI 來引用此文件:
http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/40510
完整後設資料紀錄
DC 欄位 | 值 | 語言 |
---|---|---|
dc.contributor.advisor | 許秉寧 | |
dc.contributor.author | Be-Han Lee | en |
dc.contributor.author | 李碧涵 | zh_TW |
dc.date.accessioned | 2021-06-14T16:49:44Z | - |
dc.date.available | 2018-07-28 | |
dc.date.copyright | 2008-08-08 | |
dc.date.issued | 2008 | |
dc.date.submitted | 2008-07-31 | |
dc.identifier.citation | Asagiri, M., & Takayanagi, H. (2007). The molecular understanding of osteoclast differentiation. Bone, 40(2), 251-264.
Choo, M. K., Kawasaki, N., Singhirunnusorn, P., Koizumi, K., Sato, S., Akira, S., et al. (2006). Blockade of transforming growth factor-beta-activated kinase 1 activity enhances TRAIL-induced apoptosis through activation of a caspase cascade. Mol Cancer Ther, 5(12), 2970-2976. Colucci, S., Brunetti, G., Cantatore, F. P., Oranger, A., Mori, G., Pignataro, P., et al. (2007). The death receptor DR5 is involved in TRAIL-mediated human osteoclast apoptosis. Apoptosis, 12(9), 1623-1632. Darnay, B. G., Haridas, V., Ni, J., Moore, P. A., & Aggarwal, B. B. (1998). Characterization of the intracellular domain of receptor activator of NF-kappaB (RANK). Interaction with tumor necrosis factor receptor-associated factors and activation of NF-kappab and c-Jun N-terminal kinase. J Biol Chem, 273(32), 20551-20555. David, J. P., Sabapathy, K., Hoffmann, O., Idarraga, M. H., & Wagner, E. F. (2002). JNK1 modulates osteoclastogenesis through both c-Jun phosphorylation-dependent and -independent mechanisms. J Cell Sci, 115(Pt 22), 4317-4325. Deng, L., Wang, C., Spencer, E., Yang, L., Braun, A., You, J., et al. (2000). Activation of the IkappaB kinase complex by TRAF6 requires a dimeric ubiquitin-conjugating enzyme complex and a unique polyubiquitin chain. Cell, 103(2), 351-361. Dougall, W. C., Glaccum, M., Charrier, K., Rohrbach, K., Brasel, K., De Smedt, T., et al. (1999). RANK is essential for osteoclast and lymph node development. Genes Dev, 13(18), 2412-2424. Edwards, J. R., Sun, S. G., Locklin, R., Shipman, C. M., Adamopoulos, I. E., Athanasou, N. A., et al. (2006). LIGHT (TNFSF14), a novel mediator of bone resorption, is elevated in rheumatoid arthritis. Arthritis Rheum, 54(5), 1451-1462. Huang, H., Ryu, J., Ha, J., Chang, E. J., Kim, H. J., Kim, H. M., et al. (2006). Osteoclast differentiation requires TAK1 and MKK6 for NFATc1 induction and NF-kappaB transactivation by RANKL. Cell Death Differ, 13(11), 1879-1891. Iotsova, V., Caamano, J., Loy, J., Yang, Y., Lewin, A., & Bravo, R. (1997). Osteopetrosis in mice lacking NF-kappaB1 and NF-kappaB2. Nat Med, 3(11), 1285-1289. Jin, W., Chang, M., Paul, E. M., Babu, G., Lee, A. J., Reiley, W., et al. (2008). Deubiquitinating enzyme CYLD negatively regulates RANK signaling and osteoclastogenesis in mice. J Clin Invest, 118(5), 1858-1866. Kanazawa, K., Azuma, Y., Nakano, H., & Kudo, A. (2003). TRAF5 functions in both RANKL- and TNFalpha-induced osteoclastogenesis. J Bone Miner Res, 18(3), 443-450. Kanazawa, K., & Kudo, A. (2005). Self-assembled RANK induces osteoclastogenesis ligand-independently. J Bone Miner Res, 20(11), 2053-2060. Kim, N., Kadono, Y., Takami, M., Lee, J., Lee, S. H., Okada, F., et al. (2005). Osteoclast differentiation independent of the TRANCE-RANK-TRAF6 axis. J Exp Med, 202(5), 589-595. Kim, Y. S., Schwabe, R. F., Qian, T., Lemasters, J. J., & Brenner, D. A. (2002). TRAIL-mediated apoptosis requires NF-kappaB inhibition and the mitochondrial permeability transition in human hepatoma cells. Hepatology, 36(6), 1498-1508. Kobayashi, K., Takahashi, N., Jimi, E., Udagawa, N., Takami, M., Kotake, S., et al. (2000). Tumor necrosis factor alpha stimulates osteoclast differentiation by a mechanism independent of the ODF/RANKL-RANK interaction. J Exp Med, 191(2), 275-286. Kong, Y. Y., Feige, U., Sarosi, I., Bolon, B., Tafuri, A., Morony, S., et al. (1999). Activated T cells regulate bone loss and joint destruction in adjuvant arthritis through osteoprotegerin ligand. Nature, 402(6759), 304-309. Kong, Y. Y., Yoshida, H., Sarosi, I., Tan, H. L., Timms, E., Capparelli, C., et al. (1999). OPGL is a key regulator of osteoclastogenesis, lymphocyte development and lymph-node organogenesis. Nature, 397(6717), 315-323. Lacey, D. L., Timms, E., Tan, H. L., Kelley, M. J., Dunstan, C. R., Burgess, T., et al. (1998). Osteoprotegerin ligand is a cytokine that regulates osteoclast differentiation and activation. Cell, 93(2), 165-176. Lamothe, B., Besse, A., Campos, A.D., Webster, W.K., Wu, H., and Darnay, B.G. (2007a). Site-specific Lys-63-linked tumor necrosis factor receptor-associated factor 6 auto-ubiquitination is a critical determinant of I kappa B kinase activation. The J Biol Chem, 282, 4102-4112. Lamothe, B., Webster, W.K., Gopinathan, A., Besse, A., Campos, A.D., and Darnay, B.G. (2007b). TRAF6 ubiquitin ligase is essential for RANKL signaling and osteoclast differentiation. Biochem Biophys Res Commun 359, 1044-1049. Manna, S. K., & Ramesh, G. T. (2005). Interleukin-8 induces nuclear transcription factor-kappaB through a TRAF6-dependent pathway. J Biol Chem, 280(8), 7010-7021. Matsumoto, M., Sudo, T., Saito, T., Osada, H., & Tsujimoto, M. (2000). Involvement of p38 mitogen-activated protein kinase signaling pathway in osteoclastogenesis mediated by receptor activator of NF-kappa B ligand (RANKL). J Biol Chem, 275(40), 31155-31161. Mizukami, J., Takaesu, G., Akatsuka, H., Sakurai, H., Ninomiya-Tsuji, J., Matsumoto, K., et al. (2002). Receptor activator of NF-kappaB ligand (RANKL) activates TAK1 mitogen-activated protein kinase kinase kinase through a signaling complex containing RANK, TAB2, and TRAF6. Mol Cell Biol, 22(4), 992-1000. Morel, J., Audo, R., Hahne, M., & Combe, B. (2005). Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) induces rheumatoid arthritis synovial fibroblast proliferation through mitogen-activated protein kinases and phosphatidylinositol 3-kinase/Akt. J Biol Chem, 280(16), 15709-15718. Naito, A., Azuma, S., Tanaka, S., Miyazaki, T., Takaki, S., Takatsu, K., et al. (1999). Severe osteopetrosis, defective interleukin-1 signalling and lymph node organogenesis in TRAF6-deficient mice. Genes Cells, 4(6), 353-362. Park, H., Jung, Y. K., Park, O. J., Lee, Y. J., Choi, J. Y., & Choi, Y. (2005). Interaction of Fas ligand and Fas expressed on osteoclast precursors increases osteoclastogenesis. J Immunol, 175(11), 7193-7201. Ryu, J., Kim, H. J., Chang, E. J., Huang, H., Banno, Y., & Kim, H. H. (2006). Sphingosine 1-phosphate as a regulator of osteoclast differentiation and osteoclast-osteoblast coupling. Embo J, 25(24), 5840-5851. Sato, K., Suematsu, A., Nakashima, T., Takemoto-Kimura, S., Aoki, K., Morishita, Y., et al. (2006). Regulation of osteoclast differentiation and function by the CaMK-CREB pathway. Nat Med, 12(12), 1410-1416. Secchiero, P., Gonelli, A., Mirandola, P., Melloni, E., Zamai, L., Celeghini, C., Milani, D., and Zauli, G. (2002). Tumor necrosis factor-related apoptosis-inducing ligand induces monocytic maturation of leukemic and normal myeloid precursors through a caspase-dependent pathway. Blood 100, 2421-2429. Secchiero, P., Gonelli, A., Carnevale, E., Milani, D., Pandolfi, A., Zella, D., et al. (2003). TRAIL promotes the survival and proliferation of primary human vascular endothelial cells by activating the Akt and ERK pathways. Circulation, 107(17), 2250-2256. Sedger, L. M., Glaccum, M. B., Schuh, J. C., Kanaly, S. T., Williamson, E., Kayagaki, N., et al. (2002). Characterization of the in vivo function of TNF-alpha-related apoptosis-inducing ligand, TRAIL/Apo2L, using TRAIL/Apo2L gene-deficient mice. Eur J Immunol, 32(8), 2246-2254. Shinohara, M., Koga, T., Okamoto, K., Sakaguchi, S., Arai, K., Yasuda, H., et al. (2008). Tyrosine kinases Btk and Tec regulate osteoclast differentiation by linking RANK and ITAM signals. Cell, 132(5), 794-806. Sugatani, T., & Hruska, K. A. (2005). Akt1/Akt2 and mammalian target of rapamycin/Bim play critical roles in osteoclast differentiation and survival, respectively, whereas Akt is dispensable for cell survival in isolated osteoclast precursors. J Biol Chem, 280(5), 3583-3589. Suzuki, I., & Fink, P. J. (2000). The dual functions of fas ligand in the regulation of peripheral CD8+ and CD4+ T cells. Proc Natl Acad Sci U S A, 97(4), 1707-1712. Takahashi, N., Yamana, H., Yoshiki, S., Roodman, G. D., Mundy, G. R., Jones, S. J., et al. (1988). Osteoclast-like cell formation and its regulation by osteotropic hormones in mouse bone marrow cultures. Endocrinology, 122(4), 1373-1382. Takayanagi, H. (2005). Mechanistic insight into osteoclast differentiation in osteoimmunology. J Mol Med, 83(3), 170-179. Trauzold, A., Wermann, H., Arlt, A., Schutze, S., Schafer, H., Oestern, S., et al. (2001). CD95 and TRAIL receptor-mediated activation of protein kinase C and NF-kappaB contributes to apoptosis resistance in ductal pancreatic adenocarcinoma cells. Oncogene, 20(31), 4258-4269. Wada, T., Nakashima, T., Oliveira-dos-Santos, A. J., Gasser, J., Hara, H., Schett, G., et al. (2005). The molecular scaffold Gab2 is a crucial component of RANK signaling and osteoclastogenesis. Nat Med, 11(4), 394-399. Wang, C., Deng, L., Hong, M., Akkaraju, G. R., Inoue, J., & Chen, Z. J. (2001). TAK1 is a ubiquitin-dependent kinase of MKK and IKK. Nature, 412(6844), 346-351. Wiley, S. R., Schooley, K., Smolak, P. J., Din, W. S., Huang, C. P., Nicholl, J. K., et al. (1995). Identification and characterization of a new member of the TNF family that induces apoptosis. Immunity, 3(6), 673-682. Wong, B. R., Besser, D., Kim, N., Arron, J. R., Vologodskaia, M., Hanafusa, H., et al. (1999). TRANCE, a TNF family member, activates Akt/PKB through a signaling complex involving TRAF6 and c-Src. Mol Cell, 4(6), 1041-1049. Wu, H., & Arron, J. R. (2003). TRAF6, a molecular bridge spanning adaptive immunity, innate immunity and osteoimmunology. Bioessays, 25(11), 1096-1105. Xiao, C., Yang, B. F., Song, J. H., Schulman, H., Li, L., & Hao, C. (2005). Inhibition of CaMKII-mediated c-FLIP expression sensitizes malignant melanoma cells to TRAIL-induced apoptosis. Exp Cell Res, 304(1), 244-255. Ye, H., Arron, J. R., Lamothe, B., Cirilli, M., Kobayashi, T., Shevde, N. K., et al. (2002). Distinct molecular mechanism for initiating TRAF6 signalling. Nature, 418(6896), 443-447. Yoshida, H., Hayashi, S., Kunisada, T., Ogawa, M., Nishikawa, S., Okamura, H., et al. (1990). The murine mutation osteopetrosis is in the coding region of the macrophage colony stimulating factor gene. Nature, 345(6274), 442-444. Zauli, G., Rimondi, E., Nicolin, V., Melloni, E., Celeghini, C., & Secchiero, P. (2004). TNF-related apoptosis-inducing ligand (TRAIL) blocks osteoclastic differentiation induced by RANKL plus M-CSF. Blood, 104(7), 2044-2050. Zhang, Z., Jimi, E., & Bothwell, A. L. (2003). Receptor activator of NF-kappa B ligand stimulates recruitment of SHP-1 to the complex containing TNFR-associated factor 6 that regulates osteoclastogenesis. J Immunol, 171(7), 3620-3626. | |
dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/40510 | - |
dc.description.abstract | 噬骨細胞是由血液中的單核球/巨噬細胞的前驅細胞受到receptor of nuclear factor kappa B ligand (RANKL)和macrophage colony-stimulating factor (M-CSF)的刺激,互相融合所形成巨大的多核細胞。RANKL屬於TNF family的其中一員,當RANKL與它的受體RANK結合之後,會驅使TNF receptor associated factor 6 (TRAF6)補充到RANK的細胞質內區域,並引起NF-κB與mitogen-activated protein kinase (MAPK)的活化,最後導致噬骨細胞基因的表現。除了RANKL之外,有愈來愈多證據顯示一些TNF family的成員包括TNF-α, FasL和LIGHT會去調控噬骨細胞分化及活化過程。這些研究也暗示TNF family的細胞激素可能會影響噬骨細胞的分化。
TNF-related apoptosis inducing ligand (TRAIL)亦屬於TNF family,除了會引起細胞凋亡之外,在不同的細胞也會影響細胞的增生、存活與成熟等不同的功能。我們實驗室先前的研究證實了TRAIL能夠引起人類周邊血單核細胞 (PBMCs) 與老鼠單核球/巨噬細胞的細胞株RAW 264.7 cells分化形成噬骨細胞。而我們之前的研究也發現在TRAIL引起噬骨細胞分化的過程中,可以觀察到p38, JNK, ERK與NF-κB的活化,但是TRAIL如何引起這些分子活化的機制並未研究清楚。目前已知TRAF6在RANKL引起的噬骨細胞分化過程中扮演很重要的角色,RANKL無法引起缺乏TRAF6的前驅細胞分化形成噬骨細胞。因此,我們假設TRAF6也參與在TRAIL引起的噬骨細胞分化中,並與活化下游的MAPK及NF-κB之訊息傳遞路徑有關。在本篇研究中,我們利用轉染干擾RNA的方式抑制RAW 264.7細胞中TRAF6蛋白質的表現,探討TRAF6在TRAIL引發噬骨細胞分化中所扮演的角色。我們證明了當TRAF6蛋白質表現量受到抑制時,TRAIL引起TRAP+多核細胞的形成數量會降低且細胞偏小,而TRAIL引起的p38, JNK磷酸化受到抑制。因此我們的結果證明TRAIL可以經由TRAF6傳遞活化MAPK的訊息途徑,此藉由TRAF6傳遞的訊息途徑並非導致細胞凋亡而是引發噬骨細胞的分化。 | zh_TW |
dc.description.abstract | Osteoclasts are multinucleated cells (MNCs) that are differentiated from macrophage/ monocyte lineage of hematopoietic precursors. Receptor activator of nuclear factor kappaB (NF-κB) ligand (RANKL), a tumor necrosis factor (TNF) family cytokine, plays a key role in osteoclast differentiation. RANKL binds to its receptor RANK, which recruits TNF receptor associated factor 6 (TRAF6) and activates NF-κB, Akt, and mitogen-activated protein kinase (MAPK) pathways finally leading to osteoclast-specific genes expression. In addition to RANKL, more and more studies indicated that some TNF family members including TNF-α, FasL and LIGHT are involved in differentiation and function of osteoclasts. These studies suggested that some TNF-family cytokines may regulate osteoclast differentiation.
In addition to induction of apoptosis, TNF-related apoptosis inducing ligand (TRAIL) exerts different function that includes survival, proliferation and maturation. Our previous studies have demonstrated that TRAIL can induce osteoclasts differentiation from murine monocytic cell line, RAW 264.7 and human peripheral mononuclear cells (PBMCs), and this signaling pathway is distinct from apoptosis signaling. TRAIL could activate NF-κB and MAPKs, which are important for RANKL-induced osteoclastogenesis. However, the signaling pathway that leads to downstream molecules activation and resulting in osteoclastogenesis remains unclear. TRAF6 is critical in RANKL-induced osteoclastogenesis. Cells from TRAF6-deficient mice can not differentiate into osteoclasts in the presence of RANKL. Therefore, we hypothesize that TRAIL stimulation activates MAPKs and NF-κB pathways to induce osteoclastogenesis through adaptor molecule, TRAF6. To determine whether TRAF6 is involved in TRAIL-induced osteoclastogenesis, we used TRAF6 siRNA to inhibit TRAF6 expression. After knockdown TRAF6 expression by transfection of TRAF6 siRNA, we found that similar to RANKL, osteoclast formation was reduced after TRAIL stimulation. We further investigated whether suppression of TRAF6 expression might affect TRAIL-induced NF-κB and MAPKs activation. Our results demonstrated that knockdown TRAF6 expression reduced TRAIL-induced MAPK activation. In conclusion, TRAIL induces osteoclast differentiation via activation of MAPK which is dependent on TRAF6. Our results provide a novel mechanism that TRAIL can transduce a non-apoptotic signal mediated by TRAF6 to induce osteoclast formation. | en |
dc.description.provenance | Made available in DSpace on 2021-06-14T16:49:44Z (GMT). No. of bitstreams: 1 ntu-97-R95449012-1.pdf: 1924753 bytes, checksum: f2fc5b049ef82cacba99215d588bd249 (MD5) Previous issue date: 2008 | en |
dc.description.tableofcontents | Acknowledgement i
Abstract (Chinese) ii Abstract iii Chapter Ⅰ Introduction 1 1. Osteoimmunology 1 2. Osteoclastogenesis and RANK signaling 1 3. Other molecules in osteoclast differentiation 3 Chapter II Materials and methods 5 Part 1 Experimental Materials 5 1.1 Cell lines 5 1.2 Antibodies 5 1.3 Chemicals and reagents 6 1.4 Instruments 8 Part 2 Experimental Procedures 10 2.1 His-TRAIL purification 10 2.2 Human PBMCs preparation and in vitro osteoclast differentiation 10 2.3 TRAP stain 11 2.4 siRNA interference 11 2.5 Cytosolic and nuclear extract separation 11 2.6 SDS-PAGE and Western blotting 12 2.7 Statistical analysis 12 Chapter III Results 13 Part 1: TRAIL-induced osteoclast formation from human PBMCs and murine RAW 264.7 cells 13 Part 2: TRAF6 siRNA-induced gene silencing affects TRAIL-induced osteoclastogenesis 13 Part 3: Effects of TRAF6 on TRAIL-mediated MAPK and NF-κB activation 14 Chapter Ⅳ Discussion 16 Part 1. TRAIL transmits a non-apoptotic signal to induce osteoclast differentiation. 16 Part 2. The role of TRAF6 in RANKL- and TRAIL-induced signaling pathway in osteoclast differentiation. 17 Part 3. The enigma between TRAIL- and RANKL-induced osteoclastogenesis. 19 Part 4.Conclusion 21 Reference 22 Figures 28 Figure 1. TRAIL induces osteoclast-like cell formation from human PBMCs. 29 Figure 2. TRAIL induces osteoclast-like cell formation from murine RAW 264.7 cells. 31 Figure 3. Knock down TRAF6 expression by siRNA suppresses TRAIL-induced osteoclast differentiation. 33 Figure 4. The effects of TRAF6 on RANKL- and TRAIL-induced MAPK activation. 35 Figure 5. The effects of TRAF6 on RANKL- and TRAIL-induced NF-κB activation. 37 | |
dc.language.iso | en | |
dc.title | 探討TRAF6訊息傳遞在TRAIL引發噬骨細胞分化過程之角色 | zh_TW |
dc.title | Role of TRAF6 in TRAIL-induced osteoclastogenesis | en |
dc.type | Thesis | |
dc.date.schoolyear | 96-2 | |
dc.description.degree | 碩士 | |
dc.contributor.oralexamcommittee | 司徒惠康,林琬琬 | |
dc.subject.keyword | 噬骨細胞分化,TRAIL,TRAF6, | zh_TW |
dc.subject.keyword | osteoclastogenesis,TRAIL,TRAF6, | en |
dc.relation.page | 38 | |
dc.rights.note | 有償授權 | |
dc.date.accepted | 2008-07-31 | |
dc.contributor.author-college | 醫學院 | zh_TW |
dc.contributor.author-dept | 免疫學研究所 | zh_TW |
顯示於系所單位: | 免疫學研究所 |
文件中的檔案:
檔案 | 大小 | 格式 | |
---|---|---|---|
ntu-97-1.pdf 目前未授權公開取用 | 1.88 MB | Adobe PDF |
系統中的文件,除了特別指名其著作權條款之外,均受到著作權保護,並且保留所有的權利。