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 genome-wide 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.
Highlights
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]
There is no curative therapy for OA; disease progression culminates in joint replacement surgery
We considered the expression of 14,762 genes that passed quality control (QC) across all datasets; this included 332 of 349 genes with false-discovery rate (FDR) ≤ 5% in the knee discovery data
Summary
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]. There is no curative therapy for OA; disease progression culminates in joint replacement surgery. Cartilage tissue is readily accessible at joint replacement surgery, providing an opportunity to characterize the molecular processes underpinning disease development in the right tissue, both to improve our fundamental understanding of disease biology and to identify novel therapeutic opportunities. The fundamental question here addresses the biological processes underpinning disease progression within the OA joint, which is of direct clinical relevance to patients suffering from OA. We collected individually-matched pairs of cartilage tissue from patients undergoing joint replacement surgery, with one sample demonstrating advanced degenerative change and the other demonstrating little or no evidence of cartilage degeneration. By integrating all three of methylation, gene expression, and protein abundance data, we discover disease processes with involvement across multiple levels, and reveal novel and robustly replicating molecular players with translational potential
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