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完整後設資料紀錄
DC 欄位 | 值 | 語言 |
---|---|---|
dc.contributor.advisor | 許秉寧(Ping-Ning Hsu) | |
dc.contributor.author | Hsiu-Jung Liao | en |
dc.contributor.author | 廖秀蓉 | zh_TW |
dc.date.accessioned | 2021-06-16T03:45:26Z | - |
dc.date.available | 2020-03-12 | |
dc.date.copyright | 2015-03-12 | |
dc.date.issued | 2015 | |
dc.date.submitted | 2015-02-04 | |
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dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/55048 | - |
dc.description.abstract | 蝕骨細胞是多核並具有蝕骨功能的細胞,屬於腫瘤壞死因子家族成員可與其接受體互相作用而促進蝕骨細胞分化,有許多研究已廣泛地指出RANKL的訊息機制可促進蝕骨細胞生成。RANKL活化蝕骨細胞分化中,TRAF6訊息路徑是不可或缺的,在之前的研究當中,我們的研究結果顯示TRAIL透過TRAF6訊息路徑活化蝕骨細胞分化,有趣的是,我們的結果也顯示TRAIL具有抑制RANKL以及M-CSF促進蝕骨細胞分化的現象。然而,TRAIL在RANKL或是其他腫瘤壞死因子中有無共同刺激,影響促進以及抑制蝕骨細胞分化,認為TRAIL可能在調控骨免疫學中蝕骨細胞分化中扮演重要的角色,很有可能是透過影響脂質閥以及TRAF6相關訊息,脂質閥對於聚集或排除接受器之特定訊息物質而活化免疫細胞中扮演重要的角色,我們的結果指出RANKL對於脂質閥之訊息分子傳遞而影響蝕骨細胞的功能,而TRAIL會干擾脂質閥中RANK訊息傳遞影響蝕骨細胞的分化。更進一步使用大鼠實驗性關節炎的動物模式,TRAIL不但可以改善骨密度以及骨侵蝕,更可以減少關節腫脹及發炎,然而,TRAIL抑制發炎的功能是透過抑制T細胞的活化而不是影響細胞凋亡,因此TRAIL有效地抑制實驗性關節炎的發炎以及關節炎的進展,TRAIL提供了關節炎具有潛力以及新的治療方針。
PSTPIP2參與巨噬細胞活化、噬中性白血球移動性以及蝕骨細胞分化,然而,PSTPIP2對於自體發炎以及蝕骨細胞生成的角色並不是很清楚。在我們的研究中,我們建立PSTPIP2基因剔除老鼠探討表型以及自體發炎疾病的角色,所有PSTPIP2基因剔除老鼠具有腳掌腫脹、滑膜炎、骨肥厚以及骨髓炎,類似SAPHO症候群(滑膜炎、痤瘡、膿皰病、骨肥厚、骨髓炎),發生在骨頭、皮膚以及關節的發炎疾病,多病灶性骨髓炎在發炎性腳掌中有較多的巨嗜細胞以及噬中性白血球浸潤在骨頭、關節以及皮膚,顯著性骨侵蝕的病灶部位腳掌以及肢體也發現明顯降低骨密度,在發炎的組織中也發現顯著增加趨化噬中性白血球的趨化素以及介白素-1β。我們的研究認為PSTPIP2在自體發炎骨疾病中,先天性免疫以及蝕骨細胞生成的發展扮演重要的角色,並且可能跟人類SAPHO症候群的病理具有相關性。 總而言之,我們指出TRAIL以及PSTPIP2參與蝕骨細胞活化以及發炎,認為與蝕骨細胞活化的訊息傳導路徑具有相關性,了解發炎性關節炎以及骨破壞的傳導路徑,對於骨免疫學是重要的並且可發展新的治療方式。 | zh_TW |
dc.description.abstract | Osteoclasts are bone resorbing multinucleated cells involves interactions between tumor necrosis factor (TNF) ligand superfamily members and their receptors. Accumulated evidences indicate that the signaling mechanism of RANKL in promoting osteoclasteogenesis has been extensively studied. RANKL activates TRAF6 signaling pathways, which are indispensable for the induction and activation of osteoclast differentiation. In previous study, our results have demonstrated that TRAIL induces osteoclast differentiation via a TRAF-6-dependent signaling pathway. Interestingly, our results also demonstrated that TRAIL suppressed osteoclastic differentiation induced by RANKL plus M-CSF. Therefore, TRAIL can both promote and suppress osteoclast differentiation, depending on the presence of RANKL or other TNF superfamily molecules, suggesting that TRAIL may play a role in regulating osteoclast differentiation in osteoimmunology. It is possible that the regulation is at the lipid raft and TRAF6 associated signaling. Membrane lipid rafts play a key role in immune cell activation by recruiting and excluding specific signaling components of immune cell surface receptors upon the receptor engagement. We demonstrated that rafts in osteoclasts may function as the platform for a network of signaling molecules that assemble in response to RANKL. TRAIL blocked osteoclastic differentiation was accompanied by interference the RANK signaling required the function of raft membrane microdomains. Furthermore, in collagen-induced arthritis rat animal model, treatment with TRAIL not only the improved the bone density and inhibited bone erosion, but also reduced the joint swelling and inflammation. However, the anti-inflammation effects of TRAIL inhibited T cell activation instead of increased apoptosis in T cells. Therefore, TRAIL administration is an effective anti-inflammatory treatment that prevents the development and progression of experimental arthritis. It may provide a potential and new therapeutic strategy of treatment in arthritis.
PSTPIP2 is involved in macrophage activation, neutrophil motility, and osteoclast differentiation. However, the role of PSTPIP2 in autoinflammation and osteoclastogenesis is still not clear. In our study, we generated PSTPIP2 knockout (Pstpip2-/-) mice to investigate its phenotype and role in autoinflammatory diseases. All Pstpip2-/- mice developed paw swelling, synovitis, hyperostosis, and osteitis, resembling SAPHO syndrome (synovitis, acne, pustulosis, hyperostosis, osteitis), an inflammatory disorder of the bone, skin, and joints. Multifocal osteomyelitis was found in inflamed paws with increased macrophage and marked neutrophil infiltrations in the bone, joint, and skin. Profound osteolytic lesions with marked decreased bone volume density developed in paws and limbs. Neutrophil-attracting chemokines and IL-1s were markedly elevated in inflamed tissues. Our study suggests that PSTPIP2 could play a role in innate immunity and development of osteoclastogenesis in autoinflammatory bone disorders, and may associate with the pathogenesis of human SAPHO syndrome. Taken together, we demonstrated that both TRAIL and PSTPIP2 is involved in osteoclast activation and inflammation, suggesting the cross-talk between signaling transduction pathways in osteoclast activation and inflammation. Understanding of the regulation of these pathways is important to explore the critical steps in oseoimmunology, and help to development of new therapeutic approach in inflammatory arthritis and bone destruction. | en |
dc.description.provenance | Made available in DSpace on 2021-06-16T03:45:26Z (GMT). No. of bitstreams: 1 ntu-104-D97449002-1.pdf: 12350090 bytes, checksum: cd597055e42abaf1c78b88ca9f84b7e4 (MD5) Previous issue date: 2015 | en |
dc.description.tableofcontents | 中文摘要.................................................................................................i
Abstract...............................................................................................iii Chapter I. Introduction.........................................................................1 1. The intracellular signaling mechanism of RANKL..........................1 2. TRAIL regulation in osteoclastogenesis.........................................3 3. Lipid rafts in osteoclast activation................................................4 4. TRAIL in autoimmune disease.......................................................5 5. PSTPIP2 and biological function....................................................7 6. PSTPIP2 in autoinflammatory disease mice....................................7 7. PSTPIP2 in SAPHO syndrome.........................................................9 Chapter II. Materials and methods......................................................11 Materials............................................................................................11 Methods.............................................................................................17 Chapter III. Results.............................................................................33 1. TRAIL-induced osteoclast differentiation and bone resorption activity is dependent on TRAF6...........................................................33 2. TRAIL-induced activation of MAP kinases is dependent on TRAF6................................................................................................35 3. TRAIL-induced activation of NFATc1 in osteoclastogenesis is TRAF6-dependent..............................................................................35 4. TRAIL-induced osteoclast differentiation was completely abolished in TRAF6 knock out bone marrow macrophages.................................37 5. Disruption of lipid raft integrity inhibit RANKL stimulation on NFATc1 activation and osteoclast differentiation................................38 6. TRAIL block lipid raft-associated RANK signaling molecules assembly by RANKL in osteoclasts......................................................39 7. TRAIL decrease inflammation in CIA rat model............................40 8. TRAIL reduce bone erosion in rat with CIA rat model..................42 9. TRAIL inhibit activation of T lymphocytes dose not due to apoptosis...........................................................................................43 10. PSTPIP2-deficiency mice with autoinflammatory phenotype........44 11. Pstpip2-/- mice developed synovitis, hyperostosis, multifocal osteomyelitis, and osteitis, resembling SAPHO syndrome in inflamed paws with increased macrophage numbers and abundant neutrophil infiltrations in the bone, joint, and skin..............................................46 12. Increased neutrophil infiltration in the bone marrow of inflamed paws of Pstpip2-/- mice....................................................................47 13. Significant elevation of neutrophil-attracting chemokines and IL-1 in the tissues of inflamed paws in Pstpip2-/- mice.............................48 Chapter IV. Discussions......................................................................50 1. TRAIL induced osteoclastogenesis dependent on TRAP6.............50 2. TRAIL with function as inhibitor in RANKL-induced osteoclastogenesis.............................................................................52 3. Other TNF superfamily molecules in osteoclast activation...........55 4. TRAIL blocked osteoclastic differentiation was accompanied by interference the RANK signaling.........................................................56 5. TRAIL with function as decreasing inflammation and bone erosion and apoptosis is not indispensable.....................................................58 6. SAPHO syndrome with CRMO characteristics resembles PSTPIP2-deficient mice.....................................................................................60 Chapter V. Conclusions......................................................................65 Chapter VI References........................................................................67 Chapter VII. Figures............................................................................88 Fig. 1. TRAIL induced osteoclast differentiation is dependent on TRAF6................................................................................................88 Fig. 2. TRAIL induced osteoclast resorption is dependent on TRAF6....90 Fig. 3. TRAIL induces activation of MAP Kinases is dependent on TRAF6................................................................................................91 Fig. 4. TRAIL-induced activation of NFATc1 in osteoclast differentiation is dependent on TRAF6......................................................................92 Fig. 5. TRAIL-induced osteoclast differentiation was abolished in TRAF6 knock out bone marrow-derived macrophages...................................94 Fig. 6. Raft disruption impaired integrity inhibits RANKL-induced osteoclasts differentiation..................................................................96 Fig. 7. MβCD treatment blocks RANKL-induced NFATc1 activation.....97 Fig. 8. TRAIL-TRAILR function as Lipid raft assembly associated molecules RANK-TRAF6 inhibition in RANKL-induced osteoclast activation...........................................................................................98 Fig. 9. TRAIL inhibits RANK associated molecules colocalization with GM-1 in RANKL-induced osteoclast activation....................................99 Fig. 10. TRAIL and etanercept are both effective and have synergistically effects on clinical severity in CIA rats.........................100 Fig. 11. Synergistic activity of TRAIL in combination with etanercept in the reduction of hindpaw swelling in rats with CIA............................101 Fig. 12. Inhibition of synovial membrane inflammation in rats with CIA treated with TRAIL alone and with TRAIL in combination with etanercept........................................................................................102 Fig. 13. Amelioration of severe swelling by TRAIL alone and with TRAIL in combination with etanercept in CIA rats.......................................103 Fig. 14. TRAIL significantly reduced bone density loss and increased bone mass in CIA rats.......................................................................104 Fig. 15. TRAIL significantly reduced bone density loss and increased bone mass in CIA rats.......................................................................105 Fig. 16. TRAIL decreased osteoclast numbers in CIA rats..................106 Fig. 17. TRAIL decreased serum DPD level in rats with CIA................107 Fig. 18. TRAIL significantly reduced inflammatory cytokine production in CIA rats........................................................................................108 Fig. 19. TRAIL did not induced apoptosis and cytotoxicity in activated primary T lymphocytes, synovial fibroblasts and macrophages.........109 Fig. 20. TRAIL did not induced apoptosis in synovial tissue in rats with CIA...................................................................................................110 Fig. 21. TRAIL had no apoptosis in activated T lymphocytes.............111 Fig. 22. Construction of Pstpip2 targeting vector and generation of PSTPIP2 knock-out mice...................................................................113 Fig. 23. Pstpip2-/- mice developed progressive paw swelling, erosive bone lesions, splenomegaly, and lymph node enlargement...............114 Fig. 24. Pstpip2-/- mice developed macrophage infiltration in spleen and lymph mode..............................................................................115 Fig. 25. Pstpip2-/- mice with multifocal osteomyelitis in inflamed paws and increased macrophage and marked neutrophil infiltrations in the bone, joint, and skin........................................................................116 Fig. 26. Pstpip2-/- mice developed a phenotype that erosive bone lesions.............................................................................................118 Fig. 27. Pstpip2-/- mice with decreased bone marrow density.........119 Fig. 28. Pstpip2-/- mice with decreased osteoclast activity..............120 Fig. 29. Increased CD11b+Ly6G+ (neutrophil maker) cells in the bone marrow, spleen and lymph node of Pstpip2-/- mice.........................121 Fig. 30. Increased neutrophil-attracting chemokines in Pstpip2-/- mice.................................................................................................122 Fig. 31. Increased neutrophil-attracting chemokines in Pstpip2-/- mice.................................................................................................123 Fig. 32. Increased proinflammatory cytokines from inflamed paws of Pstpip2-/- mice...............................................................................124 Fig. 33. The model of raft involvement in RANK signaling for osteoclast activation and inflammation by TRAIL in inflammatory arthritis........125 | |
dc.language.iso | en | |
dc.title | 發炎與蝕骨細胞活化訊息傳遞調控在發炎性關節炎中之研究 | zh_TW |
dc.title | Regulation of osteoclast activation and inflammation signal transduction in inflammatory arthritis | en |
dc.type | Thesis | |
dc.date.schoolyear | 103-1 | |
dc.description.degree | 博士 | |
dc.contributor.oralexamcommittee | 謝世良(Shie-Liang Hsieh),司徒惠康(Huey-Kang Sytwu),陳俊任(Chun-Jen Chen),陳念榮(Nien-Jung Chen) | |
dc.subject.keyword | 蝕骨細胞,相關凋亡誘導配體TNF,關節炎, | zh_TW |
dc.subject.keyword | Osteoclast,TRAIL,Arthritis, | en |
dc.relation.page | 125 | |
dc.rights.note | 有償授權 | |
dc.date.accepted | 2015-02-04 | |
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 |
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