title: Genome-wide DNA methylation profile implicates potential cartilage regeneration at the late stage of knee osteoarthritis.
abstract: OBJECTIVE
  The aim of this work was to characterize the genome-wide DNA methylation profile of cartilage from three regions of tibial plateau isolated from patients with primary knee osteoarthritis (OA), providing the first DNA methylation study that reflects OA progression.
  
  
  METHODS
  The unique model system was used to section three regions of tibial plateau: the outer lateral tibial plateau (oLT), the inner lateral tibial plateau (iLT) and the inner medial tibial plateau (iMT) regions which represented the early, intermediate and late stages of OA, respectively. Genome-wide DNA methylation profile was examined using Illumina Infinium HumanMethylation450 BeadChip array. Comparisons of the iLT/oLT and iMT/oLT groups were carried out to identify differentially methylated (DM) probes (DMPs) associated with OA progression. DM genes were analyzed to identify the gene ontologies (GO), pathways, upstream regulators and networks.
  
  
  RESULTS
  No significant DMPs were identified in iLT/oLT group, while 519 DMPs were identified in iMT/oLT group. Over half of them (68.2%) were hypo-methylated and enriched in enhancers and OpenSea. Upstream regulator analysis identified many microRNAs. DM genes were enriched in transcription factors, especially homeobox genes and in Wnt/β-catenin signaling pathway. These genes also showed changes in expression when analyzed with expression profiles generated from previous studies.
  
  
  CONCLUSIONS
  Our data suggested the changes in DNA methylation occurred at the late stage of OA. Pathways and networks enriched in identified DM genes highlighted potential etiologic mechanism and implicated the potential cartilage regeneration in the late stage of knee OA.
authors.affiliation: Laboratory for International Alliance on Genomic Research, Center for Integrative Medical Sciences, RIKEN, Yokohama, Japan.
authors.forename: Y
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Department of Life Sciences, Graduate School of Art and Sciences, the University of Tokyo, and Clinical Research Center, National Hospital Organization Sagamihara Hospital, Kanagawa, Japan.
authors.forename: N
authors.initials: N
authors.lastname: Fukui
authors.affiliation: Laboratory for International Alliance on Genomic Research, Center for Integrative Medical Sciences, RIKEN, Yokohama, Japan; Laboratory for Pharmacogenomics, Center for Integrative Medical Sciences, RIKEN, Yokohama, Japan.
authors.forename: M
authors.initials: M
authors.lastname: Yahata
authors.affiliation: Department of Orthopaedic Surgery, Center Hospital of the National Center for Global Health and Medicine Center Hospital, Tokyo, Japan.
authors.forename: Y
authors.initials: Y
authors.lastname: Katsuragawa
authors.affiliation: Department of Orthopaedic Surgery, Tokyo Yamate Medical Center, Tokyo, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Tashiro
authors.affiliation: Laboratory for Bone and Joint Diseases, Center for Integrative Medical Sciences, RIKEN, Tokyo, Japan.
authors.forename: S
authors.initials: S
authors.lastname: Ikegawa
authors.affiliation: Laboratory for International Alliance on Genomic Research, Center for Integrative Medical Sciences, RIKEN, Yokohama, Japan; Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan, ROC. Electronic address: mingta.lee@riken.jp.
authors.forename: M T Michael
authors.initials: MT
authors.lastname: Lee
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D002358:Cartilage, Articular / Q000378:metabolism / Q000502:physiology*; D019902:Chondrocytes / Q000378:metabolism; D019175:DNA Methylation / Q000502:physiology*; D018450:Disease Progression; D005260:Female; D005786:Gene Expression Regulation / Q000502:physiology; D063990:Gene Ontology; D016678:Genome; D055106:Genome-Wide Association Study; D006801:Humans; D007719:Knee Joint / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D020370:Osteoarthritis, Knee / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology; D012038:Regeneration / Q000235:genetics*
keywords: Cartilage; Epigenetics; Osteoarthritis; methylation