Exp Mol Med.  2015 Oct;47(10):e189. 10.1038/emm.2015.66.

miR-139 modulates MCPIP1/IL-6 expression and induces apoptosis in human OA chondrocytes

• Makki MS
• Haqqi TM

• KMID: 2160620
• DOI: http://doi.org/10.1038/emm.2015.66

Abstract

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-1beta 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.

MeSH Terms

3' Untranslated Regions
Aged
*Apoptosis
Chondrocytes/*metabolism/pathology
Down-Regulation
Female
Gene Expression Regulation
Humans
Interleukin-6/*genetics
Male
MicroRNAs/*genetics
Middle Aged
Osteoarthritis/*genetics/pathology
RNA, Messenger/genetics
Ribonucleases/*genetics
Transcription Factors/*genetics
Up-Regulation
3' Untranslated Regions
Interleukin-6
MicroRNAs
RNA, Messenger
Transcription Factors
Ribonucleases