title: Transcriptional associations of osteoarthritis-mediated loss of epigenetic control in articular cartilage.
abstract: OBJECTIVE
  To identify osteoarthritis (OA) progression-modulating pathways in articular cartilage and their respective regulatory epigenetic and genetic determinants in end-stage disease.
  
  
  METHODS
  Transcriptional activity of CpG was assessed using gene expression data and DNA methylation data for preserved and lesional articular cartilage samples. Disease-responsive transcriptionally active CpG were identified by means of differential methylation between preserved and lesional cartilage. Transcriptionally relevant genetic determinants were addressed by means of single-nucleotide polymorphisms (SNPs) proximal to the OA-responsive transcriptionally active CpG. Statistical analyses were corrected for age, sex, joint, and technical covariates. A random effect was included to correct for possible correlations between paired samples.
  
  
  RESULTS
  Of 9,838 transcribed genes in articular cartilage, 2,324 correlated with the methylation status of 3,748 transcriptionally active CpG; both negative (n = 1,741) and positive (n = 2,007) correlations were observed. Hypomethylation and hypermethylation (false discovery rate of <0.05, |Δβ| > 0.05) were observed for 62 and 25 transcriptionally active CpG, respectively, covering 70 unique genes. Enrichment for developmental and extracellular matrix maintenance pathways indicated possible reactivation of endochondral ossification. Finally, we observed 31 and 26 genes for which methylation and expression, respectively, were additionally affected by genetic variation.
  
  
  CONCLUSIONS
  We identified tissue-specific genes involved in OA disease progression, reflected by genetic and pathologic epigenetic regulation of transcription, primarily at genes involved in development. Therefore, transcriptionally active SNPs near these genes may serve as putative susceptibility alleles. Our results constitute an important step toward understanding the reported widespread epigenetic changes occurring in OA articular cartilage and toward subsequent development of treatments targeting disease-driving pathways.
authors.affiliation: Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Wouter
authors.initials: W
authors.lastname: den Hollander
authors.affiliation: Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Yolande F M
authors.initials: YF
authors.lastname: Ramos
authors.affiliation: Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Nils
authors.initials: N
authors.lastname: Bomer
authors.affiliation: Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Stefan
authors.initials: S
authors.lastname: Elzinga
authors.affiliation: Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Ruud
authors.initials: R
authors.lastname: van der Breggen
authors.affiliation: Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Nico
authors.initials: N
authors.lastname: Lakenberg
authors.affiliation: Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Wesley J
authors.initials: WJ
authors.lastname: de Dijcker
authors.affiliation: Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: H Eka D
authors.initials: HE
authors.lastname: Suchiman
authors.affiliation: Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Bouke J
authors.initials: BJ
authors.lastname: Duijnisveld
authors.affiliation: Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Jeanine J
authors.initials: JJ
authors.lastname: Houwing-Duistermaat
authors.affiliation: Leiden University Medical Center, Leiden, The Netherlands, and The Netherlands Genomics Initiative-sponsored Netherlands Consortium for Healthy Aging, Rotterdam, The Netherlands.
authors.forename: P Eline
authors.initials: PE
authors.lastname: Slagboom
authors.affiliation: Leiden University Medical Center, Leiden, The Netherlands, and The Netherlands Genomics Initiative-sponsored Netherlands Consortium for Healthy Aging, Rotterdam, The Netherlands.
authors.forename: Steffan D
authors.initials: SD
authors.lastname: Bos
authors.affiliation: Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Rob G H H
authors.initials: RG
authors.lastname: Nelissen
authors.affiliation: Leiden University Medical Center, Leiden, The Netherlands, and The Netherlands Genomics Initiative-sponsored Netherlands Consortium for Healthy Aging, Rotterdam, The Netherlands.
authors.forename: Ingrid
authors.initials: I
authors.lastname: Meulenbelt
mesh_terms: D002358:Cartilage, Articular / Q000378:metabolism*; D018899:CpG Islands; D019175:DNA Methylation; D044127:Epigenesis, Genetic / Q000235:genetics*; D005260:Female; D006801:Humans; D008297:Male; D010003:Osteoarthritis / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D059467:Transcriptome