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Downregulation of microRNA-34a* in rheumatoid arthritis synovial fibroblasts promotes apoptosis resistance


Niederer, F; Trenkmann, M; Ospelt, C; Karouzakis, E; Neidhart, M; Stanczyk, J; Kolling, C; Gay, R E; Detmar, M; Gay, S; Jüngel, A; Kyburz, D (2012). Downregulation of microRNA-34a* in rheumatoid arthritis synovial fibroblasts promotes apoptosis resistance. Arthritis and Rheumatism, 64(6):1771-1779.

Abstract

OBJECTIVE: We investigated the expression and the impact of the microRNA-34 (miR-34) family on apoptosis in synovial fibroblasts (SF) of rheumatoid arthritis (RA) patients. METHODS: Expression of the miR-34 family was analyzed by real-time PCR in SF with or without stimulation with Toll-like receptor (TLR) ligands, TNF-α, IL-1β, hypoxia and 5-azacytidine. Promoter methylation was studied by combined bisulfite restriction analysis. Overexpression and silencing of miR-34a and miR-34a* was used to analyze their effect on apoptosis by annexin V/PI staining. Production of XIAP (X-linked inhibitor of apoptosis protein) was analyzed by real-time PCR and immunohistochemistry. Reporter gene assay was used to study the signaling pathways of miR-34a*. RESULTS: Basal expression levels of miR-34a*, but not of miR-34a, miR-34b/b* and miR-34c/c*, were found to be reduced in SF from RA compared to osteoarthritis. Neither TNF-α, IL-1β, TLR ligands nor hypoxia altered miR-34a* expression. However, we identified the promoter of miR-34a/34a* to be methylated and showed that transcription of the miR-34a duplex is induced upon treatment with demethylating agents. Enforced expression of miR-34a* led to an increased rate of FasL and TRAIL mediated apoptosis in RASF. Moreover, levels of miR-34a* highly correlated with the expression of XIAP, which was found to be upregulated in RA synovial cells. Finally, our study identified XIAP as a direct target of miR-34a*. CONCLUSION: Our data provide evidence for a methylation specific downregulation of pro-apoptotic miR-34a* in RASF. Decreased expression of miR-34a* results in upregulation of its direct target XIAP, thereby contributing to apoptosis resistance of RASF.

Abstract

OBJECTIVE: We investigated the expression and the impact of the microRNA-34 (miR-34) family on apoptosis in synovial fibroblasts (SF) of rheumatoid arthritis (RA) patients. METHODS: Expression of the miR-34 family was analyzed by real-time PCR in SF with or without stimulation with Toll-like receptor (TLR) ligands, TNF-α, IL-1β, hypoxia and 5-azacytidine. Promoter methylation was studied by combined bisulfite restriction analysis. Overexpression and silencing of miR-34a and miR-34a* was used to analyze their effect on apoptosis by annexin V/PI staining. Production of XIAP (X-linked inhibitor of apoptosis protein) was analyzed by real-time PCR and immunohistochemistry. Reporter gene assay was used to study the signaling pathways of miR-34a*. RESULTS: Basal expression levels of miR-34a*, but not of miR-34a, miR-34b/b* and miR-34c/c*, were found to be reduced in SF from RA compared to osteoarthritis. Neither TNF-α, IL-1β, TLR ligands nor hypoxia altered miR-34a* expression. However, we identified the promoter of miR-34a/34a* to be methylated and showed that transcription of the miR-34a duplex is induced upon treatment with demethylating agents. Enforced expression of miR-34a* led to an increased rate of FasL and TRAIL mediated apoptosis in RASF. Moreover, levels of miR-34a* highly correlated with the expression of XIAP, which was found to be upregulated in RA synovial cells. Finally, our study identified XIAP as a direct target of miR-34a*. CONCLUSION: Our data provide evidence for a methylation specific downregulation of pro-apoptotic miR-34a* in RASF. Decreased expression of miR-34a* results in upregulation of its direct target XIAP, thereby contributing to apoptosis resistance of RASF.

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44 citations in Web of Science®
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Additional indexing

Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > University Hospital Zurich > Rheumatology Clinic and Institute of Physical Medicine
04 Faculty of Medicine > Center for Integrative Human Physiology
Dewey Decimal Classification:570 Life sciences; biology
610 Medicine & health
Language:English
Date:2012
Deposited On:29 Jan 2012 11:12
Last Modified:05 Apr 2016 15:31
Publisher:Wiley-Blackwell
ISSN:0004-3591
Publisher DOI:https://doi.org/10.1002/art.34334
PubMed ID:22161761

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