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- 2015.1
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IL-6 is an inflammatory cytokine and its overexpression plays an important role in osteoarthritis (OA) pathogenesis. Expression of IL-6 is regulated post-transcriptionally by MCPIP1. The 3′ untranslated region (UTR) of MCPIP1 mRNA harbors a miR-139 ‘seed sequence’, therefore we examined the post-transcriptional regulation of MCPIP1 by miR-139 and its impact on IL-6 expression in OA chondrocytes. Expression of miR-139 was found to be high in the damaged portion of the OA cartilage compared with unaffected cartilage from the same patient and was also induced by IL-1β in OA chondrocytes. Inhibition of miR-139 decreased the expression of IL-6 mRNA by 38% and of secreted IL-6 protein by 40%. However, overexpression of miR-139 increased the expression of IL-6 mRNA by 36% and of secreted IL-6 protein by 56%. These data correlated with altered expression profile of MCPIP1 in transfected chondrocytes. Studies with a luciferase reporter construct confirmed the interactions of miR-139 with the ‘seed sequence’ located in the 3′ UTR of MCPIP mRNA. Furthermore, miR-139 overexpression increased the catabolic gene expression but expression of anabolic markers remained unchanged. Overexpression of miR-139 also induced apoptosis in OA chondrocytes. Importantly, we also discovered that IL-6 is a potent inducer of miR-139 expression in OA chondrocytes. These findings indicate that miR-139 functions as a post-transcriptional regulator of MCPIP1 expression and enhances IL-6 expression, which further upregulates miR-139 expression in OA chondrocytes. These results support our hypothesis that miR-139-mediated downregulation of MCPIP1 promotes IL-6 expression in OA. Therefore, targeting miR-139 could be therapeutically beneficial in the management of OA.
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참고문헌 (23)
참고문헌 신청
Akhtar N / 2010 / MicroRNA-27b regulates the expression of matrix metalloproteinase 13 in human osteoarthritis chondrocytes / Arthritis Rheum 62 : 1361 ~ 1371
Akhtar N / 2015 / MicroRNA-602 and MicroRNA-608regulate sonic hedgehog expression via target sites in the coding region in human chondrocytes / Arthritis Rheumatol 67 : 423
Bartel DP. / 2004 / MicroRNAs: genomics, biogenesis, mechanism, and function / Cell 116 : 281 ~ 297
Farh KK / 2005 / The widespread impact of mammalian MicroRNAs on mRNA repression and evolution / Science 310 : 1817 ~ 1821
Goldring MB / 2012 / Epigenomic and microRNA-mediated regulation in cartilage development, homeostasis, and osteoarthritis / Trends Mol Med 18 : 109 ~ 118
Akhtar N / 2015 / MicroRNA-602 and MicroRNA-608regulate sonic hedgehog expression via target sites in the coding region in human chondrocytes / Arthritis Rheumatol 67 : 423
Bartel DP. / 2004 / MicroRNAs: genomics, biogenesis, mechanism, and function / Cell 116 : 281 ~ 297
Farh KK / 2005 / The widespread impact of mammalian MicroRNAs on mRNA repression and evolution / Science 310 : 1817 ~ 1821
Goldring MB / 2012 / Epigenomic and microRNA-mediated regulation in cartilage development, homeostasis, and osteoarthritis / Trends Mol Med 18 : 109 ~ 118
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