STAT4 recruitment following DNA demethylation in MMP-3 promoter leads to MMP-3 expression activation in articular cartilage of osteoarthritis mice

Abstract

Osteoarthritis (OA) is a multifactorial joint disease that encompasses not just cartilage deterioration but also meniscal degeneration, subchondral bone remodeling, and fibrosis of the infrapatellar fat pad and synovial membrane. OA is characterized by a progressive and irreversible loss of the articular cartilage, due in main part to the cleavage of type II collagen within the matrix by the enzyme matrix metalloproteinases (MMPs). As an important member of MMP family, MMP-3 plays a prominent role in the pathologenesis of OA. The pathological factors and signaling pathways mediating Mmp-3 expression activation during OA development are not well defined and have been a focus of intense research. Mmp-3 promoter is featured by CpG sites. So far there have been no reports concerning the functional role of DNA methylation in Mmp-3 promoter during OA development. In this study, we sought to investigate DNA methylation status in Mmp-3 promoter, the role of DNA methylation in Mmp-3 activation in OA, and the underlying mechanisms. Our results showed that Mmp-3 promoter demethylation played an important role in Mmp-3 expression activation in OA, which facilitated signal transducer and activator of transcription 4 (STAT4) binding on Mmp-3 promoter to activate Mmp-3 expression. More importantly, OA pathological phenotype of mice was alleviated in response to siRNA-mediated STAT4 knockdown. Our study illustrates how subtle changes in DNA methylation/demethylation status can directly influence gene expression and contribute to pathology and takes us one step further in the understanding of the pathogenesis of OA.