title: Genome-Wide DNA Methylation Study Identifies Significant Epigenomic Changes in Osteoarthritic Subchondral Bone and Similarity to Overlying Cartilage.
abstract: To perform a genome-wide DNA methylation study to identify differential DNA methylation patterns in subchondral bone underlying eroded and intact cartilage from patients with hip osteoarthritis (OA) and to compare these with DNA methylation patterns in overlying cartilage.
  
  
  
  Genome-wide DNA methylation profiling using Illumina HumanMethylation 450 arrays was performed on eroded and intact cartilage and subchondral bone from within the same joint of 12 patients undergoing hip arthroplasty. Genes with differentially methylated CpG sites were analyzed to identify shared pathways, upstream regulators, and overrepresented gene ontologies, and these patterns were compared with those of the overlying cartilage. Histopathology was graded by modified Mankin score and assessed for correlation with DNA methylation.
  
  
  
  We identified 7,316 differentially methylated CpG sites in subchondral bone underlying eroded cartilage, most of which (∼75%) were hypomethylated, and 1,397 sites in overlying eroded cartilage, 126 of which were shared. Samples clustered into 3 groups with distinct histopathologic scores. We observed differential DNA methylation of genes including the RNA interference-processing gene AGO2, the growth factor TGFB3, the OA suppressor NFATC1, and the epigenetic effector HDAC4. Among known susceptibility genes in OA, 32 were differentially methylated in subchondral bone, 8 were differentially methylated in cartilage, and 5 were shared. Upstream regulator analysis using differentially methylated genes in OA subchondral bone showed a strong transforming growth factor β1 signature (P = 1 × 10(-40) ) and a tumor necrosis factor family signature (P = 3.2 × 10(-28) ), among others.
  
  
  
  Our data suggest the presence of an epigenetic phenotype associated with eroded OA subchondral bone that is similar to that of overlying eroded OA cartilage.
authors.affiliation: University of Oklahoma Health Sciences Center and Oklahoma Medical Research Foundation, Oklahoma City.
authors.forename: Matlock A
authors.initials: MA
authors.lastname: Jeffries
authors.affiliation: Oklahoma Medical Research Foundation, Oklahoma City.
authors.forename: Madison
authors.initials: M
authors.lastname: Donica
authors.affiliation: University of Oklahoma, Oklahoma City.
authors.forename: Lyle W
authors.initials: LW
authors.lastname: Baker
authors.affiliation: University of Oklahoma Health Sciences Center, Oklahoma City.
authors.forename: Michael E
authors.initials: ME
authors.lastname: Stevenson
authors.affiliation: University of Oklahoma Health Sciences Center, Oklahoma City.
authors.forename: Anand C
authors.initials: AC
authors.lastname: Annan
authors.affiliation: MPH: University of Oklahoma Medical Research Center and Veterans Affairs Medical Center, Oklahoma City.
authors.forename: Mary
authors.initials: M
authors.lastname: Beth Humphrey
authors.affiliation: University of Oklahoma Health Sciences Center and Oklahoma Medical Research Foundation, Oklahoma City.
authors.forename: Judith A
authors.initials: JA
authors.lastname: James
authors.affiliation: University of Michigan, Ann Arbor.
authors.forename: Amr H
authors.initials: AH
authors.lastname: Sawalha
mesh_terms: D002358:Cartilage, Articular; D019175:DNA Methylation; D044127:Epigenesis, Genetic; D055106:Genome-Wide Association Study; D006801:Humans; D015207:Osteoarthritis, Hip / Q000235:genetics*