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系統識別號 U0026-0901201600023100
論文名稱(中文) 探討微小核糖核酸140在類風濕性關節的角色與調控
論文名稱(英文) The role of microRNA-140 and its regulation in rheumatoid joint
校院名稱 成功大學
系所名稱(中) 基礎醫學研究所
系所名稱(英) Institute of Basic Medical Sciences
學年度 104
學期 1
出版年 105
研究生(中文) 彭佳琇
研究生(英文) Jia-Shiou Peng
學號 S58961434
學位類別 博士
語文別 英文
論文頁數 87頁
口試委員 指導教授-王崇任
召集委員-吳昭良
口試委員-蕭璦莉
口試委員-劉明煇
口試委員-詹明修
口試委員-呂明錡
中文關鍵字 類風濕性關節炎  小核糖核酸140  滑液纖維母細胞  Sirtuin 1  Stromal cell-derived factor-1 
英文關鍵字 Rheumatoid arthritis  MicroRNA-140  Synovial fibroblast, Sirtuin 1  Stromal cell-derived factor-1 
學科別分類
中文摘要 在類風濕性關節炎病人的滑液纖維母細胞中,其微小核醣核酸 (microRNA, miRNA) 之不正常表現佔有很重要的致病調控角色。分析關節炎小鼠過量表現或抑制 miRNA 的表現,將能發展作為關節炎之治療。本研究中,我們假設 miR-140-3p 和 -5p 能參與類風濕性關節炎的致病過程,並且透過踝關節內注射 miR-140-3p 和 -5p 檢測能否標的至滑液纖維母細胞以改善自體免疫關節炎小鼠之病徴。在此,我們收集類風濕性關節炎病人和退化性關節炎病人的滑膜組織作為檢體,以及二種動物實驗模型-膠原蛋白誘導關節炎小鼠和膠原蛋白抗體誘導關節炎小鼠來進行本研究,並且運用慢病毒載體攜帶 precursor miR-140 (LVmiR-140) 過量表現於滑液纖維母細胞和關節炎小鼠踝關節。實驗結果顯示,在類風濕性關節炎病人的滑膜組織、膠原蛋白誘導關節炎小鼠和膠原蛋白抗體誘導關節炎小鼠之踝關節組織中,miR-140-3p 和 -5p 皆是低表現量的;在膠原蛋白誘導關節炎小鼠和膠原蛋白抗體誘導關節炎小鼠的踝關節內注射慢病毒載體攜帶 miR-140,發現能改善關節炎的臨床症狀及病理評估,並且能降低滑液纖維母細胞的密度;在膠原蛋白誘導關節炎小鼠之滑液纖維母細胞和踝關節中,發現過量表現 miR-140-3p 和 -5p 能分別降低 sirtuin 1 和 stromal cell-derived factor-1 的表現量;轉染 miR-140 至膠原蛋白誘導關節炎小鼠之滑液纖維母細胞中,發現能增加細胞凋亡、減少細胞增生和細胞移行的能力;並且進一步證實 miR-140 的表現量能受到前發炎性細胞激素的調控。我們的結果證實透過關節炎小鼠踝關節內給予 miR-140-3p 和 -5p,能標的在滑液纖維母細胞上並且作為自體免疫關節炎小鼠的治療。此研究發現能更進一步的提供類風濕性關節炎在分子治療上的藥物發展。
英文摘要 Synovial fibroblasts (SF) with aberrant expression of microRNAs (miRNA) are critical pathogenic regulators in rheumatoid arthritis (RA), and studies analyzing the effect of overexpressing or silencing miRNA expression in arthritis models can contribute to the development of miRNA-based therapeutics. We hypothesized that miR-140-3p and -5p are involved in the RA pathogenesis, and examined whether targeting SF by the intra-articular (i.a.) delivery of these molecules can ameliorate autoimmune arthritis in mice. Synovial tissues were obtained from RA patients, and two experimental models in mice were used in this study, collagen-induced arthritis (CIA) and collagen antibody-induced arthritis (CAIA). Overexpressing miR-140-3p and -5p in SF and ankle joints was performed by the lentivirus (LV)-mediated transfer of pre-miR-140 precursor molecules. Lower expression levels of miR-140-3p and -5p were detected in synovial tissues and SF from RA patients and two arthritis models. In both CIA and CAIA mice, the LV-mediated i.a. transfer of miR-140-3p and -5p ameliorated arthritis by clinical and histopathological evaluations with decrease in SF densities. Overexpressing miR-140-3p and -5p caused lower expression levels with correlated kinetic patterns of corresponding target molecules sirtuin 1 and stromal cell-derived factor-1, respectively, in SF and ankle joints. Transfection of miR-140-3p and -5p in CIA SF increased cell apoptosis, reduced proliferation responses and migration abilities, and verified the regulation of miR-140 expression by pro-inflammatory cytokines. Our results demonstrate that targeting SF by the i.a. delivery of miR-140-3p and -5p can ameliorate autoimmune arthritis, and these findings might facilitate the pharmacological development of molecular therapeutics in RA.
論文目次 Table of content

Qualified Certificate......................................I
Chinese Abstract..........................................II
Abstract.................................................III
Acknowlegements...........................................IV
Table of content...........................................V
List of figures..........................................VII
Abbreviations.............................................IX
Introduction...............................................1
Rheumatoid arthritis.......................................1
Synovial fibroblasts in rheumatoid arthritis...............3
MicroRNA and rheumatoid arthritis..........................5
MicroRNA-140 (miR-140) and rheumatoid arthritis............7
Sirtuin1 (SIRT1) and rheumatoid arthritis..................9
Stromal-derived factor-1 (SDF-1) and rheumatoid arthritis ..........................................................10
Rationale and hypothesis..................................13
Specific aims.............................................14
Materials and methods.....................................15
Clinical samples from RA and OA patients..................15
Induction of CIA and CAIA.................................15
Isolation of synovial fibroblasts (SF)....................16
Generation of lentiviral vectors..........................16
Delivery of miR-140 and evaluation of arthritis...........17
Histochemistry, immunohistochemistry, immunofluorescent and in situ hybridization (ISH)...............................17
Immunoblot assessment.....................................18
Micro-computed tomography (Micro-CT) images...............18
Quantitative real-time PCR................................19
Cell migration, apoptosis and proliferation assays........20
Enzyme-linked ImmunoSorbent Assay (ELISA) for SDF-1.......21
Statistical analysis......................................21
Results...................................................22
Decreased miR-140-3p and -5p expression in the synovial tissue of patients with rheumatoid arthritis (RA) and in the ankle joints of mice with collagen-induced arthritis (CIA) or collagen antibody-induced arthritis (CAIA).............22
Decreased miR-140-3p and -5p expression in the synovial fibroblasts (SF) from mice with collagen-induced arthritis (CIA).....................................................23
Decreased miR-140-3p and -5p expression in the ankle joints from mice with CIA compare with normal mice...............23
Amelioration of CIA by the intra-articular delivery of miR-140-3p and -5p............................................24
Overexpression of miR-140 decreased IL-6, microvessel densities and bone erosion by reducing SF in LVmiR-140-treated CIA joints........................................25
Characterization of miR-140 overexpression in synovial fibroblasts (SF)..........................................26
Regulation of miR-140 expression in synovial fibroblasts (SF)......................................................27
Expression of SIRT1 and SDF-1 target molecules in miR-140-overexpressed joints and SF...............................28
Amelioration of CAIA by the intra-articular delivery of miR-140-3p and -5p............................................30
Discussion................................................32
Conclusion................................................38
Figure legends............................................39
References................................................74
參考文獻 Abdullah, S., Scott, K., Featherstone, T., & Coady, D. (2010). Pus, pannus or tophus: coexistent rheumatoid arthritis and gout. J Clin Rheumatol. 16, 98.
Afshar, G., & Murnane, J. P. (1999). Characterization of a human gene with sequence homology to Saccharomyces cerevisiae SIR2. Gene. 234, 161-168.
Ammari, M., Jorgensen, C., & Apparailly, F. (2013). Impact of microRNAs on the understanding and treatment of rheumatoid arthritis. Curr Opin Rheumatol. 25, 225-233.
Apparailly, F., & Jorgensen, C. (2013). siRNA-based therapeutic approaches for rheumatic diseases. Nat Rev Rheumatol. 9, 56-62.
Astry, B., Harberts, E., & Moudgil, K. D. (2011). A cytokine-centric view of the pathogenesis and treatment of autoimmune arthritis. J Interferon Cytokine Res. 31, 927-940.
Audo, R., Calmon-Hamaty, F., Papon, L., Combe, B., Morel, J., & Hahne, M. (2014). Distinct effects of soluble and membrane-bound fas ligand on fibroblast-like synoviocytes from rheumatoid arthritis patients. Arthritis Rheumatol. 66, 3289-3299.
Baier, A., Meineckel, I., Gay, S., & Pap, T. (2003). Apoptosis in rheumatoid arthritis. Curr Opin Rheumatol. 15, 274-279.
Bartok, B., & Firestein, G. S. (2010). Fibroblast-like synoviocytes: key effector cells in rheumatoid arthritis. Immunol Rev. 233, 233-255.
Barton, A., & Worthington, J. (2009). Genetic susceptibility to rheumatoid arthritis: an emerging picture. Arthritis Rheum. 61, 1441-1446.
Bathon, J. M., & McMahon, D. J. (2013). Making rational treatment decisions in rheumatoid arthritis when methotrexate fails. N Engl J Med. 369, 384-385.
Bediaga, N. G., Davies, M. P., Acha-Sagredo, A., Hyde, R., Raji, O. Y., Page, R., Liloglou, T. (2013). A microRNA-based prediction algorithm for diagnosis of non-small lung cell carcinoma in minimal biopsy material. Br J Cancer. 109, 2404-2411.
Bluml, S., Bonelli, M., Niederreiter, B., Puchner, A., Mayr, G., Hayer, S., Redlich, K. (2011). Essential role of microRNA-155 in the pathogenesis of autoimmune arthritis in mice. Arthritis Rheum. 63, 1281-1288.
Bottini, N., & Firestein, G. S. (2013). Duality of fibroblast-like synoviocytes in RA: passive responders and imprinted aggressors. Nat Rev Rheumatol. 9, 24-33.
Brennan, F. M., & McInnes, I. B. (2008). Evidence that cytokines play a role in rheumatoid arthritis. J Clin Invest. 118, 3537-3545.
Buckley, C. D. (2011). Why does chronic inflammation persist: An unexpected role for fibroblasts. Immunol Lett. 138, 12-14.
Burns, J. M., Summers, B. C., Wang, Y., Melikian, A., Berahovich, R., Miao, Z., Schall, T. J. (2006). A novel chemokine receptor for SDF-1 and I-TAC involved in cell survival, cell adhesion, and tumor development. J Exp Med. 203, 2201-2213.
Carlens, C., Hergens, M. P., Grunewald, J., Ekbom, A., Eklund, A., Hoglund, C. O., & Askling, J. (2010). Smoking, use of moist snuff, and risk of chronic inflammatory diseases. Am J Respir Crit Care Med. 181, 1217-1222.
Chang, S. K., Gu, Z., & Brenner, M. B. (2010). Fibroblast-like synoviocytes in inflammatory arthritis pathology: the emerging role of cadherin-11. Immunol Rev. 233, 256-266.
Chen, H. T., Tsou, H. K., Hsu, C. J., Tsai, C. H., Kao, C. H., Fong, Y. C., & Tang, C. H. (2011). Stromal cell-derived factor-1/CXCR4 promotes IL-6 production in human synovial fibroblasts. J Cell Biochem. 112, 1219-1227.
Chen, S. Y., Shiau, A. L., Shieh, G. S., Su, C. H., Lee, C. H., Lee, H. L., Wu, C. L. (2009). Amelioration of experimental arthritis by a telomerase-dependent conditionally replicating adenovirus that targets synovial fibroblasts. Arthritis Rheum. 60, 3290-3302.
Cheng, H. L., Mostoslavsky, R., Saito, S., Manis, J. P., Gu, Y., Patel, P., Chua, K. F. (2003). Developmental defects and p53 hyperacetylation in Sir2 homolog (SIRT1)-deficient mice. Proc Natl Acad Sci U S A. 100, 10794-10799.
Chiang, D. Y., Cuthbertson, D. W., Ruiz, F. R., Li, N., & Pereira, F. A. (2013). A coregulatory network of NR2F1 and microRNA-140. PLoS One. 8, e83358.
Choy, E. (2012). Understanding the dynamics: pathways involved in the pathogenesis of rheumatoid arthritis. Rheumatology. 5, v3-11.
Choy, E. H., Kavanaugh, A. F., & Jones, S. A. (2013). The problem of choice: current biologic agents and future prospects in RA. Nat Rev Rheumatol. 9, 154-163.
Choy, E. H., Smith, C., Dore, C. J., & Scott, D. L. (2005). A meta-analysis of the efficacy and toxicity of combining disease-modifying anti-rheumatic drugs in rheumatoid arthritis based on patient withdrawal. Rheumatology. 44, 1414-1421.
Chung, Y. L., Lee, M. Y., Wang, A. J., & Yao, L. F. (2003). A therapeutic strategy uses histone deacetylase inhibitors to modulate the expression of genes involved in the pathogenesis of rheumatoid arthritis. Mol Ther. 8, 707-717.
Dai, R., Phillips, R. A., Zhang, Y., Khan, D., Crasta, O., & Ahmed, S. A. (2008). Suppression of LPS-induced Interferon-gamma and nitric oxide in splenic lymphocytes by select estrogen-regulated microRNAs: a novel mechanism of immune modulation. Blood. 112, 4591-4597.
Dai, X., Tan, Y., Cai, S., Xiong, X., Wang, L., Ye, Q., Cai, L. (2011). The role of CXCR7 on the adhesion, proliferation and angiogenesis of endothelial progenitor cells. J Cell Mol Med. 15, 1299-1309.
Das, A. M., Seynhaeve, A. L., Rens, J. A., Vermeulen, C. E., Koning, G. A., Eggermont, A. M., & Ten Hagen, T. L. (2014). Differential TIMP3 expression affects tumor progression and angiogenesis in melanomas through regulation of directionally persistent endothelial cell migration. Angiogenesis. 17, 163-177.
Davis, J. M., 3rd, & Matteson, E. L. (2009). Reumatol Clin. 5, 143-146.
De Klerck, B., Geboes, L., Hatse, S., Kelchtermans, H., Meyvis, Y., Vermeire, K., Matthys, P. (2005). Pro-inflammatory properties of stromal cell-derived factor-1 (CXCL12) in collagen-induced arthritis. Arthritis Res Ther. 7, R1208-1220.
Decaillot, F. M., Kazmi, M. A., Lin, Y., Ray-Saha, S., Sakmar, T. P., & Sachdev, P. (2011). CXCR7/CXCR4 heterodimer constitutively recruits beta-arrestin to enhance cell migration. J Biol Chem. 286, 32188-32197.
Diarra, D., Stolina, M., Polzer, K., Zwerina, J., Ominsky, M. S., Dwyer, D., Schett, G. (2007). Dickkopf-1 is a master regulator of joint remodeling. Nat Med. 13, 156-163.
Dixon, W. G., Hyrich, K. L., Watson, K. D., Lunt, M., Galloway, J., Ustianowski, A., & Symmons, D. P. (2010). Drug-specific risk of tuberculosis in patients with rheumatoid arthritis treated with anti-TNF therapy: results from the British Society for Rheumatology Biologics Register (BSRBR). Ann Rheum Dis. 69, 522-528.
Donahue, K. E., Gartlehner, G., Jonas, D. E., Lux, L. J., Thieda, P., Jonas, B. L., Lohr, K. N. (2008). Systematic review: comparative effectiveness and harms of disease-modifying medications for rheumatoid arthritis. Ann Intern Med. 148, 124-134.
Duroux-Richard, I., Jorgensen, C., & Apparailly, F. (2012). What do microRNAs mean for rheumatoid arthritis? Arthritis Rheum. 64, 11-20.
Dvir-Ginzberg, M., Gagarina, V., Lee, E. J., Booth, R., Gabay, O., & Hall, D. J. (2011). Tumor necrosis factor alpha-mediated cleavage and inactivation of SirT1 in human osteoarthritic chondrocytes. Arthritis Rheum. 63, 2363-2373.
Elshabrawy, H. A., Chen, Z., Volin, M. V., Ravella, S., Virupannavar, S., & Shahrara, S. (2015). The pathogenic role of angiogenesis in rheumatoid arthritis. Angiogenesis. 18, 433-448.
Elton, T. S., Selemon, H., Elton, S. M., & Parinandi, N. L. (2013). Regulation of the MIR155 host gene in physiological and pathological processes. Gene. 532, 1-12.
Finkel, T., Deng, C. X., & Mostoslavsky, R. (2009). Recent progress in the biology and physiology of sirtuins. Nature. 460, 587-591.
Firestein, G. S. (2003). Evolving concepts of rheumatoid arthritis. Nature. 423, 356-361.
Firestein, G. S. (2004). The T cell cometh: interplay between adaptive immunity and cytokine networks in rheumatoid arthritis. J Clin Invest. 114, 471-474.
Fulci, V., Scappucci, G., Sebastiani, G. D., Giannitti, C., Franceschini, D., Meloni, F., Macino, G. (2010). miR-223 is overexpressed in T-lymphocytes of patients affected by rheumatoid arthritis. Hum Immunol. 71, 206-211.
Gao, Z., & Ye, J. (2008). Inhibition of transcriptional activity of c-JUN by SIRT1. Biochem Biophys Res Commun. 376, 793-796.
Garcia-Vicuna, R., Gomez-Gaviro, M. V., Dominguez-Luis, M. J., Pec, M. K., Gonzalez-Alvaro, I., Alvaro-Gracia, J. M., & Diaz-Gonzalez, F. (2004). CC and CXC chemokine receptors mediate migration, proliferation, and matrix metalloproteinase production by fibroblast-like synoviocytes from rheumatoid arthritis patients. Arthritis Rheum. 50, 3866-3877.
Grabiec, A. M., Krausz, S., de Jager, W., Burakowski, T., Groot, D., Sanders, M. E., Reedquist, K. A. (2010). Histone deacetylase inhibitors suppress inflammatory activation of rheumatoid arthritis patient synovial macrophages and tissue. J Immunol. 184, 2718-2728.
Grassi, F., Cristino, S., Toneguzzi, S., Piacentini, A., Facchini, A., & Lisignoli, G. (2004). CXCL12 chemokine up-regulates bone resorption and MMP-9 release by human osteoclasts: CXCL12 levels are increased in synovial and bone tissue of rheumatoid arthritis patients. J Cell Physiol. 199, 244-251.
Ha, M., & Kim, V. N. (2014). Regulation of microRNA biogenesis. Nat Rev Mol Cell Biol. 15, 509-524.
Hah, Y. S., Cheon, Y. H., Lim, H. S., Cho, H. Y., Park, B. H., Ka, S. O., Lee, S. I. (2014). Myeloid deletion of SIRT1 aggravates serum transfer arthritis in mice via nuclear factor-kappaB activation. PLoS One. 9, e87733.
Hou, J., Wang, P., Lin, L., Liu, X., Ma, F., An, H., Cao, X. (2009). MicroRNA-146a feedback inhibits RIG-I-dependent Type I IFN production in macrophages by targeting TRAF6, IRAK1, and IRAK2. J Immunol. 183, 2150-2158.
Houtkooper, R. H., Pirinen, E., & Auwerx, J. (2012). Sirtuins as regulators of metabolism and healthspan. Nat Rev Mol Cell Biol. 13, 225-238.
Huang, W., Shang, W. L., Wang, H. D., Wu, W. W., & Hou, S. X. (2012). Sirt1 overexpression protects murine osteoblasts against TNF-alpha-induced injury in vitro by suppressing the NF-kappaB signaling pathway. Acta Pharmacol Sin. 33, 668-674.
Iborra, M., Bernuzzi, F., Invernizzi, P., & Danese, S. (2012). MicroRNAs in autoimmunity and inflammatory bowel disease: crucial regulators in immune response. Autoimmun Rev. 11, 305-314.
Jude, J. A., Dileepan, M., Subramanian, S., Solway, J., Panettieri, R. A., Jr., Walseth, T. F., & Kannan, M. S. (2012). miR-140-3p regulation of TNF-alpha-induced CD38 expression in human airway smooth muscle cells. Am J Physiol Lung Cell Mol Physiol. 303, L460-468.
Kanbe, K., Takagishi, K., & Chen, Q. (2002). Stimulation of matrix metalloprotease 3 release from human chondrocytes by the interaction of stromal cell-derived factor 1 and CXC chemokine receptor 4. Arthritis Rheum. 46, 130-137.
Karlsen, T. A., Jakobsen, R. B., Mikkelsen, T. S., & Brinchmann, J. E. (2014). microRNA-140 targets RALA and regulates chondrogenic differentiation of human mesenchymal stem cells by translational enhancement of SOX9 and ACAN. Stem Cells Dev. 23, 290-304.
Kiener, H. P., Niederreiter, B., Lee, D. M., Jimenez-Boj, E., Smolen, J. S., & Brenner, M. B. (2009). Cadherin 11 promotes invasive behavior of fibroblast-like synoviocytes. Arthritis Rheum. 60, 1305-1310.
Kim, H. R., Kim, K. W., Kim, B. M., Jung, H. G., Cho, M. L., & Lee, S. H. (2014). Reciprocal activation of CD4+ T cells and synovial fibroblasts by stromal cell-derived factor 1 promotes RANKL expression and osteoclastogenesis in rheumatoid arthritis. Arthritis Rheumatol. 66, 538-548.
Koch, A. E., Kunkel, S. L., Harlow, L. A., Mazarakis, D. D., Haines, G. K., Burdick, M. D., Strieter, R. M. (1994). Epithelial neutrophil activating peptide-78: a novel chemotactic cytokine for neutrophils in arthritis. J Clin Invest. 94, 1012-1018.
Koch, A. E., Kunkel, S. L., Shah, M. R., Hosaka, S., Halloran, M. M., Haines, G. K., Strieter, R. M. (1995). Growth-related gene product alpha. A chemotactic cytokine for neutrophils in rheumatoid arthritis. J Immunol. 155, 3660-3666.
Koch, A. E., Volin, M. V., Woods, J. M., Kunkel, S. L., Connors, M. A., Harlow, L. A., Strieter, R. M. (2001). Regulation of angiogenesis by the C-X-C chemokines interleukin-8 and epithelial neutrophil activating peptide 78 in the rheumatoid joint. Arthritis Rheum. 44, 31-40.
Kok, S. H., Lin, L. D., Hou, K. L., Hong, C. Y., Chang, C. C., Hsiao, M., Lin, S. K. (2013). Simvastatin inhibits cysteine-rich protein 61 expression in rheumatoid arthritis synovial fibroblasts through the regulation of sirtuin-1/FoxO3a signaling. Arthritis Rheum. 65, 639-649.
Kong, S., Yeung, P., & Fang, D. (2013). The class III histone deacetylase sirtuin 1 in immune suppression and its therapeutic potential in rheumatoid arthritis. J Genet Genomics. 40, 347-354.
Kortesidis, A., Zannettino, A., Isenmann, S., Shi, S., Lapidot, T., & Gronthos, S. (2005). Stromal-derived factor-1 promotes the growth, survival, and development of human bone marrow stromal stem cells. Blood. 105, 3793-3801.
Kurowska-Stolarska, M., Alivernini, S., Ballantine, L. E., Asquith, D. L., Millar, N. L., Gilchrist, D. S., McInnes, I. B. (2011). MicroRNA-155 as a proinflammatory regulator in clinical and experimental arthritis. Proc Natl Acad Sci U S A. 108, 11193-11198.
Lee, A., Qiao, Y., Grigoriev, G., Chen, J., Park-Min, K. H., Park, S. H., Kalliolias, G. D. (2013). Tumor necrosis factor alpha induces sustained signaling and a prolonged and unremitting inflammatory response in rheumatoid arthritis synovial fibroblasts. Arthritis Rheum. 65, 928-938.
Leombruno, J. P., Einarson, T. R., & Keystone, E. C. (2009). The safety of anti-tumour necrosis factor treatments in rheumatoid arthritis: meta and exposure-adjusted pooled analyses of serious adverse events. Ann Rheum Dis. 68, 1136-1145.
Levoye, A., Balabanian, K., Baleux, F., Bachelerie, F., & Lagane, B. (2009). CXCR7 heterodimerizes with CXCR4 and regulates CXCL12-mediated G protein signaling. Blood. 113, 6085-6093.
Li, J., Wan, Y., Guo, Q., Zou, L., Zhang, J., Fang, Y., Wu, Y. (2010). Altered microRNA expression profile with miR-146a upregulation in CD4+ T cells from patients with rheumatoid arthritis. Arthritis Res Ther. 12, R81.
Li, Y. T., Chen, S. Y., Wang, C. R., Liu, M. F., Lin, C. C., Jou, I. M., Wu, C. L. (2012). Brief report: amelioration of collagen-induced arthritis in mice by lentivirus-mediated silencing of microRNA-223. Arthritis Rheum. 64, 3240-3245.
Li, Z., & Rana, T. M. (2014). Therapeutic targeting of microRNAs: current status and future challenges. Nat Rev Drug Discov. 13, 622-638.
Liang, B., Yin, J. J., & Zhan, X. R. (2015). miR-301a promotes cell proliferation by directly targeting TIMP2 in multiple myeloma. Int J Clin Exp Pathol. 8, 9168-9174.
Lie, S., Morrison, J. L., Williams-Wyss, O., Suter, C. M., Humphreys, D. T., Ozanne, S. E., McMillen, I. C. (2015). Impact of maternal undernutrition around the time of conception on factors regulating hepatic lipid metabolism and microRNAs in singleton and twin fetuses. Am J Physiol Endocrinol Metab. ajpendo 00600 02014.
Lin, H. S., Hu, C. Y., Chan, H. Y., Liew, Y. Y., Huang, H. P., Lepescheux, L., Clement-Lacroix, P. (2007). Anti-rheumatic activities of histone deacetylase (HDAC) inhibitors in vivo in collagen-induced arthritis in rodents. Br J Pharmacol. 150, 862-872.
Lochhead, R. B., Ma, Y., Zachary, J. F., Baltimore, D., Zhao, J. L., Weis, J. H., Weis, J. J. (2014). MicroRNA-146a provides feedback regulation of lyme arthritis but not carditis during infection with Borrelia burgdorferi. PLoS Pathog. 10, e1004212.
Massa, A., Casagrande, S., Bajetto, A., Porcile, C., Barbieri, F., Thellung, S., Florio, T. (2006). SDF-1 controls pituitary cell proliferation through the activation of ERK1/2 and the Ca2+-dependent, cytosolic tyrosine kinase Pyk2. Ann N Y Acad Sci. 1090, 385-398.
Matsumoto, S., Muller-Ladner, U., Gay, R. E., Nishioka, K., & Gay, S. (1996). Ultrastructural demonstration of apoptosis, Fas and Bcl-2 expression of rheumatoid synovial fibroblasts. J Rheumatol. 23, 1345-1352.
McInnes, I. B., & Schett, G. (2011). The pathogenesis of rheumatoid arthritis. N Engl J Med. 365, 2205-2219.
Miyaki, S., Nakasa, T., Otsuki, S., Grogan, S. P., Higashiyama, R., Inoue, A., Asahara, H. (2009). MicroRNA-140 is expressed in differentiated human articular chondrocytes and modulates interleukin-1 responses. Arthritis Rheum. 60, 2723-2730.
Miyaki, S., Sato, T., Inoue, A., Otsuki, S., Ito, Y., Yokoyama, S., Asahara, H. (2010). MicroRNA-140 plays dual roles in both cartilage development and homeostasis. Genes Dev. 24, 1173-1185.
Monaco, C., Nanchahal, J., Taylor, P., & Feldmann, M. (2015). Anti-TNF therapy: past, present and future. Int Immunol. 27, 55-62.
Moon, M. H., Jeong, J. K., Lee, Y. J., Seol, J. W., Jackson, C. J., & Park, S. Y. (2013). SIRT1, a class III histone deacetylase, regulates TNF-alpha-induced inflammation in human chondrocytes. Osteoarthritis Cartilage. 21, 470-480.
Muller-Ladner, U., Gay, R. E., & Gay, S. (2000). Activation of synoviocytes. Curr Opin Rheumatol. 12, 186-194.
Murata, K., Yoshitomi, H., Tanida, S., Ishikawa, M., Nishitani, K., Ito, H., & Nakamura, T. (2010). Plasma and synovial fluid microRNAs as potential biomarkers of rheumatoid arthritis and osteoarthritis. Arthritis Res Ther. 12, R86.
Nagasawa, T., Hirota, S., Tachibana, K., Takakura, N., Nishikawa, S., Kitamura, Y., Kishimoto, T. (1996). Defects of B-cell lymphopoiesis and bone-marrow myelopoiesis in mice lacking the CXC chemokine PBSF/SDF-1. Nature. 382, 635-638.
Nakamachi, Y., Kawano, S., Takenokuchi, M., Nishimura, K., Sakai, Y., Chin, T., Kumagai, S. (2009). MicroRNA-124a is a key regulator of proliferation and monocyte chemoattractant protein 1 secretion in fibroblast-like synoviocytes from patients with rheumatoid arthritis. Arthritis Rheum. 60, 1294-1304.
Nakamura, T., Kukita, T., Shobuike, T., Nagata, K., Wu, Z., Ogawa, K., Kukita, A. (2005). Inhibition of histone deacetylase suppresses osteoclastogenesis and bone destruction by inducing IFN-beta production. J Immunol. 175, 5809-5816.
Nakamura, Y., Inloes, J. B., Katagiri, T., & Kobayashi, T. (2011). Chondrocyte-specific microRNA-140 regulates endochondral bone development and targets Dnpep to modulate bone morphogenetic protein signaling. Mol Cell Biol. 31, 3019-3028.
Nanki, T., Hayashida, K., El-Gabalawy, H. S., Suson, S., Shi, K., Girschick, H. J., Lipsky, P. E. (2000). Stromal cell-derived factor-1-CXC chemokine receptor 4 interactions play a central role in CD4+ T cell accumulation in rheumatoid arthritis synovium. J Immunol. 165, 6590-6598.
Nanki, T., Nagasaka, K., Hayashida, K., Saita, Y., & Miyasaka, N. (2001). Chemokines regulate IL-6 and IL-8 production by fibroblast-like synoviocytes from patients with rheumatoid arthritis. J Immunol. 167, 5381-5385.
Nicolas, F. E., Pais, H., Schwach, F., Lindow, M., Kauppinen, S., Moulton, V., & Dalmay, T. (2008). Experimental identification of microRNA-140 targets by silencing and overexpressing miR-140. RNA. 14, 2513-2520.
Niederer, F., Ospelt, C., Brentano, F., Hottiger, M. O., Gay, R. E., Gay, S., Kyburz, D. (2011). SIRT1 overexpression in the rheumatoid arthritis synovium contributes to proinflammatory cytokine production and apoptosis resistance. Ann Rheum Dis. 70, 1866-1873.
Niederer, F., Trenkmann, M., Ospelt, C., Karouzakis, E., Neidhart, M., Stanczyk, J., Kyburz, D. (2012). Down-regulation of microRNA-34a* in rheumatoid arthritis synovial fibroblasts promotes apoptosis resistance. Arthritis Rheum. 64, 1771-1779.
Niimoto, T., Nakasa, T., Ishikawa, M., Okuhara, A., Izumi, B., Deie, M., Ochi, M. (2010). MicroRNA-146a expresses in interleukin-17 producing T cells in rheumatoid arthritis patients. BMC Musculoskelet Disord. 11, 209.
Nishida, K., Komiyama, T., Miyazawa, S., Shen, Z. N., Furumatsu, T., Doi, H., Asahara, H. (2004). Histone deacetylase inhibitor suppression of autoantibody-mediated arthritis in mice via regulation of p16INK4a and p21(WAF1/Cip1) expression. Arthritis Rheum. 50, 3365-3376.
Norii, M., Yamamura, M., Iwahashi, M., Ueno, A., Yamana, J., & Makino, H. (2006). Selective recruitment of CXCR3+ and CCR5+ CCR4+ T cells into synovial tissue in patients with rheumatoid arthritis. Acta Med Okayama. 60, 149-157.
Oppenheimer, H., Gabay, O., Meir, H., Haze, A., Kandel, L., Liebergall, M., Dvir-Ginzberg, M. (2012). 75-kd sirtuin 1 blocks tumor necrosis factor alpha-mediated apoptosis in human osteoarthritic chondrocytes. Arthritis Rheum. 64, 718-728.
Orimo, A., Gupta, P. B., Sgroi, D. C., Arenzana-Seisdedos, F., Delaunay, T., Naeem, R., Weinberg, R. A. (2005). Stromal fibroblasts present in invasive human breast carcinomas promote tumor growth and angiogenesis through elevated SDF-1/CXCL12 secretion. Cell. 121, 335-348.
Osiri, M., Shea, B., Robinson, V., Suarez-Almazor, M., Strand, V., Tugwell, P., & Wells, G. (2003). Leflunomide for the treatment of rheumatoid arthritis: a systematic review and metaanalysis. J Rheumatol. 30, 1182-1190.
Pablos, J. L., Santiago, B., Galindo, M., Torres, C., Brehmer, M. T., Blanco, F. J., & Garcia-Lazaro, F. J. (2003). Synoviocyte-derived CXCL12 is displayed on endothelium and induces angiogenesis in rheumatoid arthritis. J Immunol. 170, 2147-2152.
Pandis, I., Ospelt, C., Karagianni, N., Denis, M. C., Reczko, M., Camps, C., Kollias, G. (2012). Identification of microRNA-221/222 and microRNA-323-3p association with rheumatoid arthritis via predictions using the human tumour necrosis factor transgenic mouse model. Ann Rheum Dis. 71, 1716-1723.
Pando, R., Even-Zohar, N., Shtaif, B., Edry, L., Shomron, N., Phillip, M., & Gat-Yablonski, G. (2012). MicroRNAs in the growth plate are responsive to nutritional cues: association between miR-140 and SIRT1. J Nutr Biochem. 23, 1474-1481.
Papaioannou, G., Mirzamohammadi, F., Lisse, T. S., Nishimori, S., Wein, M. N., & Kobayashi, T. (2015). MicroRNA-140 Provides Robustness to the Regulation of Hypertrophic Chondrocyte Differentiation by the PTHrP-HDAC4 Pathway. J Bone Miner Res. 30, 1044-1052.
Pauley, K. M., Satoh, M., Chan, A. L., Bubb, M. R., Reeves, W. H., & Chan, E. K. (2008). Upregulated miR-146a expression in peripheral blood mononuclear cells from rheumatoid arthritis patients. Arthritis Res Ther. 10, R101.
Paunovic, V., & Harnett, M. M. (2013). Mitogen-activated protein kinases as therapeutic targets for rheumatoid arthritis. Drugs. 73, 101-115.
Preyat, N., & Leo, O. (2013). Sirtuin deacylases: a molecular link between metabolism and immunity. J Leukoc Biol. 93, 669-680.
Rakoczy, J., Fernandez-Valverde, S. L., Glazov, E. A., Wainwright, E. N., Sato, T., Takada, S., Wilhelm, D. (2013). MicroRNAs-140-5p/140-3p modulate Leydig cell numbers in the developing mouse testis. Biol Reprod. 88, 143.
Revesz, L., Blum, E., Di Padova, F. E., Buhl, T., Feifel, R., Gram, H., Rucklin, G. (2004). Novel p38 inhibitors with potent oral efficacy in several models of rheumatoid arthritis. Bioorg Med Chem Lett. 14, 3595-3599.
Scally, S. W., Petersen, J., Law, S. C., Dudek, N. L., Nel, H. J., Loh, K. L., Rossjohn, J. (2013). A molecular basis for the association of the HLA-DRB1 locus, citrullination, and rheumatoid arthritis. J Exp Med. 210, 2569-2582.
Schaefer, J. S., Montufar-Solis, D., Vigneswaran, N., & Klein, J. R. (2011). Selective upregulation of microRNA expression in peripheral blood leukocytes in IL-10-/- mice precedes expression in the colon. J Immunol. 187, 5834-5841.
Scrivo, R., Vasile, M., Bartosiewicz, I., & Valesini, G. (2011). Inflammation as "common soil" of the multifactorial diseases. Autoimmun Rev. 10, 369-374.
Selmi, C., Generali, E., Massarotti, M., Bianchi, G., & Scire, C. A. (2014). New treatments for inflammatory rheumatic disease. Immunol Res. 60, 277-288.
Shibuya, H., Nakasa, T., Adachi, N., Nagata, Y., Ishikawa, M., Deie, M., Ochi, M. (2013). Overexpression of microRNA-223 in rheumatoid arthritis synovium controls osteoclast differentiation. Mod Rheumatol. 23, 674-685.
Shigeyama, Y., Pap, T., Kunzler, P., Simmen, B. R., Gay, R. E., & Gay, S. (2000). Expression of osteoclast differentiation factor in rheumatoid arthritis. Arthritis Rheum. 43, 2523-2530.
Singh, J. A., Christensen, R., Wells, G. A., Suarez-Almazor, M. E., Buchbinder, R., Lopez-Olivo, M. A., Tugwell, P. (2009). A network meta-analysis of randomized controlled trials of biologics for rheumatoid arthritis: a Cochrane overview. CMAJ. 181, 787-796.
Smolen, J. S., Aletaha, D., Koeller, M., Weisman, M. H., & Emery, P. (2007). New therapies for treatment of rheumatoid arthritis. Lancet. 370, 1861-1874.
Smolen, J. S., & Steiner, G. (2003). Therapeutic strategies for rheumatoid arthritis. Nat Rev Drug Discov. 2, 473-488.
Solomon, J. M., Pasupuleti, R., Xu, L., McDonagh, T., Curtis, R., DiStefano, P. S., & Huber, L. J. (2006). Inhibition of SIRT1 catalytic activity increases p53 acetylation but does not alter cell survival following DNA damage. Mol Cell Biol. 26, 28-38.
Stanczyk, J., Ospelt, C., Karouzakis, E., Filer, A., Raza, K., Kolling, C., Kyburz, D. (2011). Altered expression of microRNA-203 in rheumatoid arthritis synovial fibroblasts and its role in fibroblast activation. Arthritis Rheum. 63, 373-381.
Stanczyk, J., Pedrioli, D. M., Brentano, F., Sanchez-Pernaute, O., Kolling, C., Gay, R. E., Kyburz, D. (2008). Altered expression of MicroRNA in synovial fibroblasts and synovial tissue in rheumatoid arthritis. Arthritis Rheum. 58, 1001-1009.
Suarez-Almazor, M. E., Belseck, E., Shea, B., Wells, G., & Tugwell, P. (2000). Methotrexate for rheumatoid arthritis. Cochrane Database Syst Rev. 2, CD000957.
Swanson, C. D., Akama-Garren, E. H., Stein, E. A., Petralia, J. D., Ruiz, P. J., Edalati, A., Robinson, W. H. (2012). Inhibition of epidermal growth factor receptor tyrosine kinase ameliorates collagen-induced arthritis. J Immunol. 188, 3513-3521.
Swingler, T. E., Wheeler, G., Carmont, V., Elliott, H. R., Barter, M. J., Abu-Elmagd, M., Clark, I. M. (2012). The expression and function of microRNAs in chondrogenesis and osteoarthritis. Arthritis Rheum. 64, 1909-1919.
Szekanecz, Z., Haines, G. K., Lin, T. R., Harlow, L. A., Goerdt, S., Rayan, G., & Koch, A. E. (1994). Differential distribution of intercellular adhesion molecules (ICAM-1, ICAM-2, and ICAM-3) and the MS-1 antigen in normal and diseased human synovia. Their possible pathogenetic and clinical significance in rheumatoid arthritis. Arthritis Rheum. 37, 221-231.
Szekanecz, Z., Pakozdi, A., Szentpetery, A., Besenyei, T., & Koch, A. E. (2009). Chemokines and angiogenesis in rheumatoid arthritis. Front Biosci. 1, 44-51.
Taganov, K. D., Boldin, M. P., Chang, K. J., & Baltimore, D. (2006). NF-kappaB-dependent induction of microRNA miR-146, an inhibitor targeted to signaling proteins of innate immune responses. Proc Natl Acad Sci U S A. 103, 12481-12486.
Takata, A., Otsuka, M., Kojima, K., Yoshikawa, T., Kishikawa, T., Yoshida, H., & Koike, K. (2011). MicroRNA-22 and microRNA-140 suppress NF-kappaB activity by regulating the expression of NF-kappaB coactivators. Biochem Biophys Res Commun. 411, 826-831.
Tang, Z., Yang, Y., Wang, Z., Zhao, S., Mu, Y., & Li, K. (2015). Integrated analysis of miRNA and mRNA paired expression profiling of prenatal skeletal muscle development in three genotype pigs. Sci Rep. 5, 15544.
Tardif, G., Pelletier, J. P., Fahmi, H., Hum, D., Zhang, Y., Kapoor, M., & Martel-Pelletier, J. (2013). NFAT3 and TGF-beta/SMAD3 regulate the expression of miR-140 in osteoarthritis. Arthritis Res Ther. 15, R197.
Tolboom, T. C., Pieterman, E., van der Laan, W. H., Toes, R. E., Huidekoper, A. L., Nelissen, R. G., Huizinga, T. W. (2002). Invasive properties of fibroblast-like synoviocytes: correlation with growth characteristics and expression of MMP-1, MMP-3, and MMP-10. Ann Rheum Dis. 61, 975-980.
Trenkmann, M., Brock, M., Gay, R. E., Michel, B. A., Gay, S., & Huber, L. C. (2013). Tumor necrosis factor alpha-induced microRNA-18a activates rheumatoid arthritis synovial fibroblasts through a feedback loop in NF-kappaB signaling. Arthritis Rheum. 65, 916-927.
Turner, J. D., & Filer, A. (2015). The role of the synovial fibroblast in rheumatoid arthritis pathogenesis. Curr Opin Rheumatol. 27, 175-182.
Van den Brand, B. T., Abdollahi-Roodsaz, S., Bennink, M. B., Bussink, J., Arntz, O. J., van den Berg, W. B., & van de Loo, F. A. (2013). Toll-like receptor 4 in bone marrow-derived cells as well as tissue-resident cells participate in aggravating autoimmune destructive arthritis. Ann Rheum Dis. 72, 1407-1415.
Villalvilla, A., Gomez, R., Roman-Blas, J. A., Largo, R., & Herrero-Beaumont, G. (2014). SDF-1 signaling: a promising target in rheumatic diseases. Expert Opin Ther Targets. 18, 1077-1087.
Volin, M. V., & Koch, A. E. (2011). Interleukin-18: a mediator of inflammation and angiogenesis in rheumatoid arthritis. J Interferon Cytokine Res. 31, 745-751.
Wang, P., Guo, X., Zong, W., Song, B., Liu, G., & He, S. (2015). MicroRNA-128b suppresses tumor growth and promotes apoptosis by targeting A2bR in gastric cancer. Biochem Biophys Res Commun. 467, 798-804.
Watanabe, K., Penfold, M. E., Matsuda, A., Ohyanagi, N., Kaneko, K., Miyabe, Y., Nanki, T. (2010). Pathogenic role of CXCR7 in rheumatoid arthritis. Arthritis Rheum. 62, 3211-3220.
Wei, J., Bhattacharyya, S., Tourtellotte, W. G., & Varga, J. (2011). Fibrosis in systemic sclerosis: emerging concepts and implications for targeted therapy. Autoimmun Rev. 10, 267-275.
Wei, L., Sun, X., Kanbe, K., Wang, Z., Sun, C., Terek, R., & Chen, Q. (2006). Chondrocyte death induced by pathological concentration of chemokine stromal cell-derived factor-1. J Rheumatol. 33, 1818-1826.
Williams, P. J., Nishu, K., & Rahman, M. M. (2011). HDAC inhibitor trichostatin A suppresses osteoclastogenesis by upregulating the expression of C/EBP-beta and MKP-1. Ann N Y Acad Sci. 1240, 18-25.
Wright, L. M., Maloney, W., Yu, X., Kindle, L., Collin-Osdoby, P., & Osdoby, P. (2005). Stromal cell-derived factor-1 binding to its chemokine receptor CXCR4 on precursor cells promotes the chemotactic recruitment, development and survival of human osteoclasts. Bone. 36, 840-853.
Xing, Q., de Vos, P., Faas, M. M., Ye, Q., & Ren, Y. (2011). LPS promotes pre-osteoclast activity by up-regulating CXCR4 via TLR-4. J Dent Res. 90, 157-162.
Yang, H., Fang, F., Chang, R., & Yang, L. (2013). MicroRNA-140-5p suppresses tumor growth and metastasis by targeting transforming growth factor beta receptor 1 and fibroblast growth factor 9 in hepatocellular carcinoma. Hepatology. 58, 205-217.
Yang, J. S., Phillips, M. D., Betel, D., Mu, P., Ventura, A., Siepel, A. C., Lai, E. C. (2011). Widespread regulatory activity of vertebrate microRNA* species. RNA. 17, 312-326.
Yeung, F., Hoberg, J. E., Ramsey, C. S., Keller, M. D., Jones, D. R., Frye, R. A., & Mayo, M. W. (2004). Modulation of NF-kappaB-dependent transcription and cell survival by the SIRT1 deacetylase. EMBO J. 23, 2369-2380.
Yu, X., Huang, Y., Collin-Osdoby, P., & Osdoby, P. (2003). Stromal cell-derived factor-1 (SDF-1) recruits osteoclast precursors by inducing chemotaxis, matrix metalloproteinase-9 (MMP-9) activity, and collagen transmigration. J Bone Miner Res. 18, 1404-1418.
Yuan, J., Minter-Dykhouse, K., & Lou, Z. (2009). A c-Myc-SIRT1 feedback loop regulates cell growth and transformation. J Cell Biol. 185, 203-211.
Zabel, B. A., Wang, Y., Lewen, S., Berahovich, R. D., Penfold, M. E., Zhang, P., Schall, T. J. (2009). Elucidation of CXCR7-mediated signaling events and inhibition of CXCR4-mediated tumor cell transendothelial migration by CXCR7 ligands. J Immunol. 183, 3204-3211.
Zhu, S., Pan, W., Song, X., Liu, Y., Shao, X., Tang, Y., Qian, Y. (2012). The microRNA miR-23b suppresses IL-17-associated autoimmune inflammation by targeting TAB2, TAB3 and IKK-alpha. Nat Med. 18, 1077-1086.
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