Abstract
SummaryObjectivesJoint degeneration in osteoarthritis (OA) is characterised by damage and loss of articular cartilage. The pattern of loss is consistent with damage occurring only where the mechanical loading is high. We have investigated using RNA-sequencing (RNA-seq) and systems analyses the changes that occur in damaged OA cartilage by comparing it with intact cartilage from the same joint.MethodsCartilage was obtained from eight OA patients undergoing total knee replacement. RNA was extracted from cartilage on the damaged distal medial condyle (DMC) and the intact posterior lateral condyle (PLC). RNA-seq was performed to identify differentially expressed genes (DEGs) and systems analyses applied to identify dysregulated pathways.ResultsIn the damaged OA cartilage, there was decreased expression of chondrogenic genes SOX9, SOX6, COL11A2, COL9A1/2/3, ACAN and HAPLN1; increases in non-chondrogenic genes COL1A1, COMP and FN1; an altered pattern of secreted proteinase expression; but no expression of major inflammatory cytokines. Systems analyses by PhenomeExpress revealed significant sub-networks of DEGs including mitotic cell cycle, Wnt signalling, apoptosis and matrix organisation that were influenced by a core of altered transcription factors (TFs), FOSL1, AHR, E2F1 and FOXM1.ConclusionsGene expression changes in damaged cartilage suggested a signature non-chondrogenic response of altered matrix protein and secreted proteinase expression. There was evidence of a damage response in this late OA cartilage, which surprisingly showed features detected experimentally in the early response of cartilage to mechanical overload. PhenomeExpress analysis identified a hub of DEGs linked by a core of four differentially regulated TFs.
Highlights
Osteoarthritis (OA) is a major cause of pain and disability in older adults, constituting a significant economic burden which is increasing with an ageing population
RNA-seq analysis was performed on the eight paired OA distal medial condyle (DMC) and posterior lateral condyle (PLC) samples and after normalisation and correction for multiple testing we identified 830 genes significantly upregulated and 745 genes significantly down-regulated (4.8 and 4.3% respectively of the total genes analysed) in the damaged cartilage relative to the intact (Supplementary Fig. 1)
Matrix protein gene expression changes As the integrity of the matrix is clearly important in OA cartilage, it was noticeable that many extracellular matrix (ECM) genes were amongst the most highly expressed genes in both DMC and PLC samples (22 of the top 50), suggesting both sites have strong matrix production
Summary
Osteoarthritis (OA) is a major cause of pain and disability in older adults, constituting a significant economic burden which is increasing with an ageing population. OA is a heterogeneous disease in which there are multiple mechanisms contributing to joint failure, including, misalignment/deformity, muscle weakness, ligament laxity, subchondral bone sclerosis/cysts and osteophyte formation, but one common outcome is cartilage damage and loss[2]. S.L. Dunn et al / Osteoarthritis and Cartilage 24 (2016) 1431e1440 from intact and damaged sites within the same joint to identify changes in gene expression which may contribute to intact cartilage becoming damaged. Dunn et al / Osteoarthritis and Cartilage 24 (2016) 1431e1440 from intact and damaged sites within the same joint to identify changes in gene expression which may contribute to intact cartilage becoming damaged This paired analysis of samples from the same joint minimises confounding variables in patient age and genetics and increases the power of the study[4,5]. Identifying genes and regulatory pathways involved as OA cartilage becomes damaged may provide new targets for treatment to delay or reverse the damage
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