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MicroRNA-9 Promotion of Interleukin-6 Expression by Inhibiting Monocyte Chemoattractant Protein-Induced Protein 1 Expression in Interleukin-1β-Stimulated Human Chondrocytes.
- Source :
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Arthritis & Rheumatology . Aug2015, Vol. 67 Issue 8, p2117-2128. 12p. - Publication Year :
- 2015
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Abstract
- Objective Enhanced expression of interleukin-6 (IL-6) plays an important role in the pathogenesis of osteoarthritis (OA). Monocyte chemoattractant protein-induced protein 1 (MCPIP-1) is a novel posttranscriptional regulator of IL-6 expression and is targeted by microRNA-9 (miR-9). We investigated the expression of MCPIP-1 in OA cartilage and explored whether targeting of MCPIP-1 by miR-9 contributes to enhanced IL-6 expression in OA. Methods Gene and protein expression in IL-1β-stimulated human OA chondrocytes/cartilage was determined by TaqMan assay and immunoblotting, respectively. Messenger RNA (mRNA) for MCPIP-1 and IL-6 expression at the single-cell level was analyzed using RNAscope. MCPIP-1 protein interaction with IL-6 mRNA was investigated using RNA immunoprecipitation. Transient transfections were used for the small interfering RNA (siRNA)-mediated knockdown and overexpression of MCPIP-1, its RNase-defective mutant miR-9, or antagomir. The role of signaling pathways was evaluated using small-molecule inhibitors. Binding of miR-9 with the 'seed sequence' in the 3′-untranslated region of MCPIP-1 mRNA was investigated using a luciferase reporter assay. Results MCPIP-1 mRNA expression was low, but expression of miR-9 and IL-6 was high, in damaged OA cartilage. In IL-1β-stimulated OA chondrocytes, the expression of miR-9 and MCPIP-1 was mutually exclusive, and increased expression of miR-9 correlated with reduced MCPIP-1 expression and enhanced IL-6 expression. MCPIP-1 protein directly binds with IL-6 mRNA, and overexpression of wild-type MCPIP-1 destabilized the IL-6 mRNA. MCPIP-1 expression was altered by overexpression or inhibition of miR-9. Transfection with miR-9 mimics inhibited the reporter activity, and mutation of the 'seed sequence' abolished the repression of reporter activity. Conclusion These findings implicate miR-9-mediated suppression of MCPIP-1 in the pathogenesis of OA via up-regulation of IL-6 expression in IL-1β-stimulated human OA chondrocytes. [ABSTRACT FROM AUTHOR]
Details
- Language :
- English
- ISSN :
- 23265191
- Volume :
- 67
- Issue :
- 8
- Database :
- Academic Search Index
- Journal :
- Arthritis & Rheumatology
- Publication Type :
- Academic Journal
- Accession number :
- 108580273
- Full Text :
- https://doi.org/10.1002/art.39173