Expression of ADAMTS-4 by chondrocytes in the surface zone of human osteoarthritic cartilage is regulated by epigenetic DNA de-methylation

Kelvin S.C. Cheung, Ko Hashimoto, Norikazu Yamada, Helmtrud I. Roach

    Research output: Contribution to journalArticlepeer-review

    83 Citations (Scopus)

    Abstract

    The two major aggrecanases involved in osteoarthritis (OA) are ADAMTS-4 and ADAMTS-5. Knock-out studies suggested that ADAMTS-5, but not ADAMTS-4, is the major aggrecanase in murine OA. However, studies of human articular cartilage suggest that ADAMTS-4 also contributes to aggrecan degradation in human OA. This study investigated ADAMTS-4 in human OA. While ADAMTS-4 was virtually absent in control cartilage, numerous ADAMTS-4 immuno-positive chondrocytes were present in OA cartilage and their numbers increased with disease severity. RT-PCR confirmed expression, especially in the surface zone. DNA methylation was lost at specific CpG sites in the ADAMTS-4 promoter in OA chondrocytes, suggesting that the increased gene expression was more than a simple up-regulation, but involved loss of DNA methylation at specific CpG sites, resulting in a heritable and permanent expression of ADAMTS-4 in OA chondrocytes. These results suggest that ADAMTS-4 is epigenetically regulated and plays a role in aggrecan degradation in human OA.

    Original languageEnglish
    Pages (from-to)525-534
    Number of pages10
    JournalRheumatology International
    Volume29
    Issue number5
    DOIs
    Publication statusPublished - 2009 Mar

    Keywords

    • ADAMTS-4
    • DNA methylation
    • Gene expression
    • Histology
    • Immunocytochemistry
    • Osteoarthritis

    ASJC Scopus subject areas

    • Rheumatology
    • Immunology and Allergy
    • Immunology

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