RT Journal Article
SR Electronic
T1 Integrative epigenomics, transcriptomics and proteomics of patient chondrocytes reveal genes and pathways involved in osteoarthritis
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 038067
DO 10.1101/038067
A1 Julia Steinberg
A1 Graham R. S. Ritchie
A1 Theodoros I. Roumeliotis
A1 Raveen L. Jayasuriya
A1 Roger A. Brooks
A1 Abbie L. A. Binch
A1 Karan M. Shah
A1 Rachael Coyle
A1 Mercedes Pardo
A1 Christine L. Le Maitre
A1 Yolande F. M. Ramos
A1 Rob G. H. H. Nelissen
A1 Ingrid Meulenbelt
A1 Andrew W. McCaskie
A1 Jyoti S. Choudhary
A1 J. Mark Wilkinson
A1 Eleftheria Zeggini
YR 2016
UL http://biorxiv.org/content/early/2016/11/30/038067.abstract
AB Background Osteoarthritis (OA) is a common disease characterized by cartilage degeneration and joint remodeling. The underlying molecular changes underpinning disease progression are incompletely understood, but can be characterized using recent advances in genomics technologies, as the relevant tissue is readily accessible at joint replacement surgery. Here we investigate genes and pathways that mark OA progression, combining genome-wide DNA methylation, RNA sequencing and quantitative proteomics in isolated primary chondrocytes from matched intact and degraded articular cartilage samples across twelve patients with OA undergoing knee replacement surgery.Results We identify 49 genes differentially regulated between intact and degraded cartilage at multiple omics levels, 16 of which have not previously been implicated in OA progression. Using independent replication datasets, we replicate statistically significant signals and show that the direction of change is consistent for over 90% of differentially expressed genes and differentially methylated CpG probes. Three genes are differentially regulated across all 3 omics levels: AQP1, COL1A1 and CLEC3B, and all three have evidence implicating them in OA through animal or cellular model studies. Integrated pathway analysis implicates the involvement of extracellular matrix degradation, collagen catabolism and angiogenesis in disease progression. All data from these experiments are freely available as a resource for the scientific community.Conclusions This work provides a first integrated view of the molecular landscape of human primary chondrocytes and identifies key molecular players in OA progression that replicate across independent datasets, with evidence for translational potential.