The expression and function of microRNAs in chondrogenesis and osteoarthritis

Tracey E. Swingler, Guy Wheeler, Virginia Carmont, Hannah R. Elliott, Matthew J. Barter, Muhammad Abu-Elmagd, Simon T. Donell, Raymond P. Boot-Handford, Mohammad K. Hajihosseini, Andrea Münsterberg, Tamas Dalmay, David A. Young, Ian M. Clark

    Research output: Contribution to journalArticlepeer-review

    Abstract

    Objective To use an in vitro model of chondrogenesis to identify microRNAs (miRNAs) with a functional role in cartilage homeostasis. Methods The expression of miRNAs was measured in the ATDC5 cell model of chondrogenesis using microarray and was verified using quantitative reverse transcription-polymerase chain reaction. MicroRNA expression was localized by in situ hybridization. Predicted miRNA target genes were validated using 3'-untranslated region-Luc reporter plasmids containing either wild-type sequences or mutants of the miRNA target sequence. Signaling through the Smad pathway was measured using a (CAGA) 12-Luc reporter. Results The expression of several miRNAs was regulated during chondrogenesis. These included 39 miRNAs that are coexpressed with miRNA-140 (miR-140), which is known to be involved in cartilage homeostasis and osteoarthritis (OA). Of these miRNAs, miR-455 resides within an intron of COL27A1 that encodes a cartilage collagen. When human OA cartilage was compared with cartilage obtained from patients with femoral neck fractures, the expression of both miR-140-5p and miR-455-3p was increased in OA cartilage. In situ hybridization showed miR-455-3p expression in the developing limbs of chicks and mice and in human OA cartilage. The expression of miR-455-3p was regulated by transforming growth factor β (TGFβ) ligands, and miRNA regulated TGFβ signaling. ACVR2B, SMAD2, and CHRDL1 were direct targets of miR-455-3p and may mediate its functional impact on TGFβ signaling. Conclusion MicroRNA-455 is expressed during chondrogenesis and in adult articular cartilage, where it can regulate TGFβ signaling, suppressing the Smad2/3 pathway. Diminished signaling through this pathway during the aging process and in OA chondrocytes is known to contribute to cartilage destruction. We propose that the increased expression of miR-455 in OA exacerbates this process and contributes to disease pathology. Copyright © 2012 by the American College of Rheumatology.
    Original languageEnglish
    Pages (from-to)1909-1919
    Number of pages10
    JournalArthritis Care & Research
    Volume64
    Issue number6
    DOIs
    Publication statusPublished - Jun 2012

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