Differential DNA methylation and expression of inflammatory and zinc transporter genes defines subgroups of osteoarthritic hip patients

OBJECTIVES: We have previously shown that the cartilage DNA methylome delineates two clusters of osteoarthritic (OA) hip patients, characterised by differential methylation of inflammatory genes, while others have demonstrated a link between zinc homeostasis and inflammation in OA. We aimed to investigate these effects at the methylation and gene expression level. METHODS: We used our previously generated methylation data while quantitative PCR was used to measure gene expression using RNA from the hip cartilage of members of both clusters and from control individuals without hip OA. RESULTS: One of the OA clusters is characterised by the promoter hypomethylation and increased expression of inflammation-associated genes including IL1A and TNF. Furthermore, we show that the increase in expression of these genes is accompanied by increased expression of several zinc transporter genes. In addition, the zinc responsive transcription factor MTF1 is also upregulated, which is accompanied by an increase in the expression of its targets the metalloproteinases MMP13 and ADAMTS5. CONCLUSIONS: We have identified a subgroup of OA hip patients that are epigenetically and transcriptiomically characterised by a cartilage inflammatory phenotype with concurrent differential regulation of zinc regulators. The identification of subgroups enhances stratified phenotyping of OA patients and has important implications for future therapeutic applications.