Chondrocyte miRNAs 221 and 483-5p respond to loss of matrix interaction by modulating proliferation and matrix synthesis.

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Connective tissue research


AIM: The purpose of this study was to identify the microRNAs that regulate the response of chondrocytes to loss of matrix interaction.

MATERIALS AND METHODS: MicroRNA and gene expression was compared in bovine cartilage and isolated chondrocytes using array analysis. Those microRNAs showing more than three-fold change in expression were verified by quantitative PCR after a stem-loop reverse transcription in bovine and human cartilage, and chondrocytes. Their function was investigated using target gene reporter construct expression, quantification of cell proliferation, and analysis of gene expression and matrix synthesis after transfection with microRNA mimics.

RESULTS: Only four microRNAs were confirmed to have a greater than three-fold change in expression after isolation of bovine or human chondrocytes from their extracellular matrix; miRs-221, -222 and -21 showed increased expression and miR-483-5p showed decreased expression. Transfection with a miR-221 mimic was shown to suppress expression of the cyclin-dependent kinase inhibitor p27 leading to the stimulation of chondrocyte proliferation. Transfection of chondrocytes with a miR-483-5p mimic was shown to suppress several members of the mitogen activated protein kinase (MAPK) pathway; a likely explanation of the increased matrix production observed.

CONCLUSIONS: microRNAs 221 and 483-5p respond to the loss of chondrocyte matrix interaction by respectively stimulating proliferation by suppression of inhibitors of cell division and suppression of matrix production possibly by release of inhibition of the MAPK pathway.

Medical Subject Headings

Animals; Cartilage, Articular; Cattle; Cell Proliferation; Chondrocytes; Extracellular Matrix; Gene Expression; Humans; MicroRNAs; Signal Transduction

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