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Amelioration of Experimental Autoimmune Arthritis Through Targeting of Synovial Fibroblasts by Intraarticular Delivery of MicroRNAs 140-3p and 140-5p.
Arthritis Rheumatol. 2016 Feb; 68(2):370-81.AR

Abstract

OBJECTIVE

Synovial fibroblasts (SFs) with aberrant expression of microRNAs (miRNAs) 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 therapeutic strategies. This study was undertaken to examine the hypothesis that miRNAs 140-3p and 140-5p are involved in the pathogenesis of RA, and to determine whether targeting SFs through the intraarticular (IA) delivery of these molecules could ameliorate autoimmune arthritis in mice.

METHODS

Synovial tissue samples were obtained from patients with RA. In addition, 2 experimental models in mice were used, collagen-induced arthritis (CIA) and collagen antibody-induced arthritis (CAIA). Overexpression of miRNAs 140-3p and 140-5p in SFs and synovial tissue was induced using lentivirus (LV)-mediated transfer of pre-miR-140 precursor molecules.

RESULTS

Lower expression levels of miR-140-3p and miR-140-5p were detected in synovial tissue and SFs from patients with RA and from mice in both arthritis models. In mice with CIA and mice with CAIA, the LV-mediated IA transfer of miR-140-3p and miR-140-5p ameliorated arthritis, as determined by clinical examination and histopathologic evaluations showing a decrease in SF densities. Overexpression of miRNAs 140-3p and 140-5p caused a reduction in expression, with correlated kinetic patterns, of their corresponding target molecules sirtuin 1 and stromal cell-derived factor 1 in the SFs and joints of mice. Transfection of miR-140-3p and miR-140-5p into SFs increased cell apoptosis, reduced proliferation responses and migration abilities, and verified the concept that miR-140 expression is regulated by proinflammatory cytokines.

CONCLUSION

These results demonstrate that targeting SFs by IA delivery of miRNAs 140-3p and 140-5p can ameliorate autoimmune arthritis. These findings might facilitate the pharmacologic development of molecular-based therapies in RA.

Links

Publisher Full Text (DOI)

Authors+Show Affiliations

Peng JS
National Cheng Kung University Medical College, Tainan, Taiwan.
Chen SY
National Cheng Kung University Medical College, Tainan, Taiwan.
Wu CL
National Cheng Kung University Medical College, Tainan, Taiwan.
Chong HE
National Cheng Kung University Medical College, Tainan, Taiwan.
Ding YC
National Cheng Kung University Medical College, Tainan, Taiwan.
Shiau AL
National Cheng Kung University Medical College, Tainan, Taiwan.
Wang CR
National Cheng Kung University Medical College, Tainan, Taiwan.

MeSH

AnimalsApoptosisArthritis, ExperimentalArthritis, RheumatoidAutoimmune DiseasesCase-Control StudiesCell MovementCell ProliferationFibroblastsFluorescent Antibody TechniqueGene ExpressionGene Transfer TechniquesHumansImmunohistochemistryIn Situ HybridizationInjections, Intra-ArticularMaleMiceMice, Inbred DBAMicroRNAsOsteoarthritisReal-Time Polymerase Chain ReactionSynovial MembraneTransfectionX-Ray Microtomography

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

26473405

Citation

Peng, Jia-Shiou, et al. "Amelioration of Experimental Autoimmune Arthritis Through Targeting of Synovial Fibroblasts By Intraarticular Delivery of MicroRNAs 140-3p and 140-5p." Arthritis & Rheumatology (Hoboken, N.J.), vol. 68, no. 2, 2016, pp. 370-81.
Peng JS, Chen SY, Wu CL, et al. Amelioration of Experimental Autoimmune Arthritis Through Targeting of Synovial Fibroblasts by Intraarticular Delivery of MicroRNAs 140-3p and 140-5p. Arthritis Rheumatol. 2016;68(2):370-81.
Peng, J. S., Chen, S. Y., Wu, C. L., Chong, H. E., Ding, Y. C., Shiau, A. L., & Wang, C. R. (2016). Amelioration of Experimental Autoimmune Arthritis Through Targeting of Synovial Fibroblasts by Intraarticular Delivery of MicroRNAs 140-3p and 140-5p. Arthritis & Rheumatology (Hoboken, N.J.), 68(2), 370-81. https://doi.org/10.1002/art.39446
Peng JS, et al. Amelioration of Experimental Autoimmune Arthritis Through Targeting of Synovial Fibroblasts By Intraarticular Delivery of MicroRNAs 140-3p and 140-5p. Arthritis Rheumatol. 2016;68(2):370-81. PubMed PMID: 26473405.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Amelioration of Experimental Autoimmune Arthritis Through Targeting of Synovial Fibroblasts by Intraarticular Delivery of MicroRNAs 140-3p and 140-5p. AU - Peng,Jia-Shiou, AU - Chen,Shih-Yao, AU - Wu,Chao-Liang, AU - Chong,Hao-Earn, AU - Ding,Yun-Chiao, AU - Shiau,Ai-Li, AU - Wang,Chrong-Reen, PY - 2015/03/12/received PY - 2015/09/17/accepted PY - 2015/10/17/entrez PY - 2015/10/17/pubmed PY - 2016/6/15/medline SP - 370 EP - 81 JF - Arthritis & rheumatology (Hoboken, N.J.) JO - Arthritis Rheumatol VL - 68 IS - 2 N2 - OBJECTIVE: Synovial fibroblasts (SFs) with aberrant expression of microRNAs (miRNAs) 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 therapeutic strategies. This study was undertaken to examine the hypothesis that miRNAs 140-3p and 140-5p are involved in the pathogenesis of RA, and to determine whether targeting SFs through the intraarticular (IA) delivery of these molecules could ameliorate autoimmune arthritis in mice. METHODS: Synovial tissue samples were obtained from patients with RA. In addition, 2 experimental models in mice were used, collagen-induced arthritis (CIA) and collagen antibody-induced arthritis (CAIA). Overexpression of miRNAs 140-3p and 140-5p in SFs and synovial tissue was induced using lentivirus (LV)-mediated transfer of pre-miR-140 precursor molecules. RESULTS: Lower expression levels of miR-140-3p and miR-140-5p were detected in synovial tissue and SFs from patients with RA and from mice in both arthritis models. In mice with CIA and mice with CAIA, the LV-mediated IA transfer of miR-140-3p and miR-140-5p ameliorated arthritis, as determined by clinical examination and histopathologic evaluations showing a decrease in SF densities. Overexpression of miRNAs 140-3p and 140-5p caused a reduction in expression, with correlated kinetic patterns, of their corresponding target molecules sirtuin 1 and stromal cell-derived factor 1 in the SFs and joints of mice. Transfection of miR-140-3p and miR-140-5p into SFs increased cell apoptosis, reduced proliferation responses and migration abilities, and verified the concept that miR-140 expression is regulated by proinflammatory cytokines. CONCLUSION: These results demonstrate that targeting SFs by IA delivery of miRNAs 140-3p and 140-5p can ameliorate autoimmune arthritis. These findings might facilitate the pharmacologic development of molecular-based therapies in RA. SN - 2326-5205 UR - https://www.unboundmedicine.com/medline/citation/26473405/Amelioration_of_Experimental_Autoimmune_Arthritis_Through_Targeting_of_Synovial_Fibroblasts_by_Intraarticular_Delivery_of_MicroRNAs_140_3p_and_140_5p_ DB - PRIME DP - Unbound Medicine ER -