title: miR-139 modulates MCPIP1/IL-6 expression and induces apoptosis in human OA chondrocytes.
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-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.
authors.affiliation: Department of Anatomy and Neurobiology, Northeast Ohio Medical University, Rootstown, OH USA.
authors.forename: Mohammad Shahidul
authors.initials: MS
authors.lastname: Makki
authors.affiliation: Department of Anatomy and Neurobiology, Northeast Ohio Medical University, Rootstown, OH USA.
authors.forename: Tariq M
authors.initials: TM
authors.lastname: Haqqi
mesh_terms: D020413:3' Untranslated Regions; D000368:Aged; D017209:Apoptosis; D019902:Chondrocytes / Q000378:metabolism* / Q000473:pathology; D015536:Down-Regulation; D005260:Female; D005786:Gene Expression Regulation; D006801:Humans; D015850:Interleukin-6 / Q000235:genetics*; D008297:Male; D035683:MicroRNAs / Q000235:genetics*; D008875:Middle Aged; D010003:Osteoarthritis / Q000235:genetics* / Q000473:pathology; D012333:RNA, Messenger / Q000235:genetics; D012260:Ribonucleases / Q000235:genetics*; D014157:Transcription Factors / Q000235:genetics*; D015854:Up-Regulation
chemical_list: D020413:3' Untranslated Regions; C508600:IL6 protein, human; D015850:Interleukin-6; C555098:MIRN139 microRNA, human; D035683:MicroRNAs; D012333:RNA, Messenger; D014157:Transcription Factors; D012260:Ribonucleases; C510646:ZC3H12A protein, human