title: Genome-wide DNA methylation study identifies significant epigenomic changes in osteoarthritic cartilage.
abstract: OBJECTIVE
  To perform a genome-wide DNA methylation study to identify DNA methylation changes in osteoarthritic (OA) cartilage tissue.
  
  
  METHODS
  The contribution of differentially methylated genes to OA pathogenesis was assessed by bioinformatic analysis, gene expression analysis, and histopathologic severity correlation. Genome-wide DNA methylation profiling of >485,000 methylation sites was performed on eroded and intact cartilage from within the same joint of 24 patients undergoing hip arthroplasty for OA. Genes with differentially methylated CpG sites were analyzed to identify overrepresented gene ontologies, pathways, and upstream regulators. The messenger RNA expression of a subset of differentially methylated genes was analyzed by reverse transcription-polymerase chain reaction. Histopathology was graded by modified Mankin score and correlated with DNA methylation.
  
  
  RESULTS
  We identified 550 differentially methylated sites in OA. Most (69%) were hypomethylated and enriched among gene enhancers. We found differential methylation in genes with prior links to OA, including RUNX1, RUNX2, DLX5, FURIN, HTRA1, FGFR2, NFATC1, SNCAIP, and COL11A2. Among these, RUNX1, HTRA1, FGFR2, and COL11A2 were also differentially expressed. Furthermore, we found differential methylation in approximately one-third of known OA susceptibility genes. Among differentially methylated genes, upstream regulator analysis showed enrichment of TGFB1 (P = 4.40 × 10(-5) ) and several microRNAs including miR-128 (P = 4.48 × 10(-13) ), miR-27a (P = 4.15 × 10(-12) ), and miR-9 (P = 9.20 × 10(-10) ). Finally, we identified strong correlations between 20 CpG sites and the histologic Mankin score in OA.
  
  
  CONCLUSIONS
  Our data implicate epigenetic dysregulation of a host of genes and pathways in OA, including a number of OA susceptibility genes. Furthermore, we identified correlations between CpG methylation and histologic severity in OA.
authors: University of Oklahoma Health Sciences Center and Oklahoma Medical Research Foundation, Oklahoma City.
authors: Matlock A
authors: MA
authors: Jeffries
authors: Madison
authors: M
authors: Donica
authors: Lyle W
authors: LW
authors: Baker
authors: Michael E
authors: ME
authors: Stevenson
authors: Anand C
authors: AC
authors: Annan
authors: Mary Beth
authors: MB
authors: Humphrey
authors: Judith A
authors: JA
authors: James
authors: Amr H
authors: AH
authors: Sawalha
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002358:Cartilage, Articular / Q000378:metabolism* / Q000473:pathology; D019175:DNA Methylation; D005260:Female; D006621:Hip Joint / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D008297:Male; D008875:Middle Aged; D015207:Osteoarthritis, Hip / Q000235:genetics* / Q000378:metabolism / Q000473:pathology