title: Differential DNA methylation and expression of inflammatory and zinc transporter genes defines subgroups of osteoarthritic hip patients.
abstract: OBJECTIVE
  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.
authors: Musculoskeletal Research Group, Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, UK.
authors: Michael D
authors: MD
authors: Rushton
authors: Musculoskeletal Research Group, Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, UK.
authors: David A
authors: DA
authors: Young
authors: Musculoskeletal Research Group, Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, UK.
authors: John
authors: J
authors: Loughlin
authors: Musculoskeletal Research Group, Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, UK.
authors: Louise N
authors: LN
authors: Reynard
mesh_terms: D051722:ADAM Proteins / Q000235:genetics; D000071116:ADAMTS5 Protein; D000368:Aged; D000369:Aged, 80 and over; D002358:Cartilage, Articular / Q000378:metabolism*; D016022:Case-Control Studies; D019175:DNA Methylation; D004268:DNA-Binding Proteins / Q000235:genetics; D044127:Epigenesis, Genetic; D005260:Female; D005786:Gene Expression Regulation; D006801:Humans; D053582:Interleukin-1alpha / Q000235:genetics; D008297:Male; D053509:Matrix Metalloproteinase 13 / Q000235:genetics; D008875:Middle Aged; D015207:Osteoarthritis, Hip / Q000235:genetics*; D012333:RNA, Messenger / Q000378:metabolism*; D014157:Transcription Factors / Q000235:genetics; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics; D015854:Up-Regulation; D000097809:Transcription Factor MTF-1
chemical_list: D051722:ADAM Proteins; D000071116:ADAMTS5 Protein; D004268:DNA-Binding Proteins; D053582:Interleukin-1alpha; D053509:Matrix Metalloproteinase 13; D012333:RNA, Messenger; D014157:Transcription Factors; D014409:Tumor Necrosis Factor-alpha; D000097809:Transcription Factor MTF-1; C508584:IL1A protein, human; C121532:ADAMTS5 protein, human; C507079:MMP13 protein, human
keywords: Chondrocytes; Inflammation; Osteoarthritis