Integrative epigenomics, transcriptomics and proteomics of patient chondrocytes reveal genes and pathways involved in osteoarthritis

Abstract

Osteoarthritis (OA) is a common disease characterized by cartilage degeneration and joint remodeling. The underlying molecular changes underpinning disease progression are incompletely understood. We investigated genes and pathways that mark OA progression in isolated primary chondrocytes taken from paired intact versus degraded articular cartilage samples across 38 patients undergoing joint replacement surgery (discovery cohort: 12 knee OA, replication cohorts: 17 knee OA, 9 hip OA patients). We combined genome-wide DNA methylation, RNA sequencing, and quantitative proteomics data. We identified 49 genes differentially regulated between intact and degraded cartilage in at least two -omics levels, 16 of which have not previously been implicated in OA progression. Integrated pathway analysis implicated the involvement of extracellular matrix degradation, collagen catabolism and angiogenesis in disease progression. Using independent replication datasets, we showed that the direction of change is consistent for over 90% of differentially expressed genes and differentially methylated CpG probes. AQP1, COL1A1 and CLEC3B were significantly differentially regulated across all three -omics levels, confirming their differential expression in human disease. Through integration of genomewide methylation, gene and protein expression data in human primary chondrocytes, we identified consistent molecular players in OA progression that replicated across independent datasets and that have translational potential.Osteoarthritis (OA) affects in excess of 40% of individuals over the age of 70 years 1 , and is a leading cause of pain and loss of physical function 2 . The molecular mechanisms underlying OA remain incompletely understood and

Evaluation of shared genetic aetiology between osteoarthritis and bone mineral density identifies SMAD3 as a novel osteoarthritis risk locus

“…Using RNA sequencing data, we confirmed the expression of SMAD3 in low-grade degenerate articular cartilage of 12 knee and 9 hip OA patients undergoing total joint replacement ( 26 ) ( Supplementary Material, Fig. S5 ).…”

Genetics of osteoarthritis

“…2, sections A to H). Such datasets have proved invaluable to the OA and musculoskeletal research community and include gene and transcript expression data 38,39 , foetal and aged chromatin accessibility data (ATACseq) 40,41 , chromatin state data (ChIP-seq) 42 , long range chromatin interactions (Capture HiC) 43 , and DNA methylation (DNAm) Please cite this article as: Aubourg G et al, Genetics of osteoarthritis, Osteoarthritis and Cartilage, https://doi.org/10.1016/j.joca.2021.03.002 data 44e48 . The inclusion of such data into post-GWAS analysis helps to assign a biological function to OA-associated variants.…”

Phenotypic instability of chondrocytes in osteoarthritis: on a path to hypertrophy

“…Numerous studies have revealed the importance of DNA methylation in controlling the expression of chondrocyte‐specific genes, such as COL9A1 , and genes encoding proteinases, including MMPs and ADAMTSs, in some cases via methylation of the promoter sequences that bind trans ‐acting factors . Studies integrating transcriptomics, epigenomics, and proteomics data from human OA chondrocytes have uncovered pathways differentially modulated in OA disease . One study has shown an overall increase in methylation accompanied by reduced expression of transcription factors in OA compared to healthy cartilage .…”