Stratification of knee osteoarthritis: two major patient subgroups identified by genome-wide expression analysis of articular cartilage

Abstract

IntroductionOsteoarthritis (OA) is a heterogeneous and complex disease. We have used a network biology approach based on genome-wide analysis of gene expression in OA knee cartilage to seek evidence for pathogenic mechanisms that may distinguish different patient subgroups.MethodsResults from RNA-Sequencing (RNA-Seq) were collected from intact knee cartilage at total knee replacement from 44 patients with OA, from 16 additional patients with OA and 10 control patients with non-OA. Results were analysed to identify patient subsets and compare major active pathways.ResultsThe RNA-Seq results showed 2692 differentially expressed genes between OA and non-OA. Analysis by unsupervised clustering identified two distinct OA groups: Group A with 24 patients (55%) and Group B with 18 patients (41%). A 10 gene subgroup classifier was validated by RT-qPCR in 16 further patients with OA. Pathway analysis showed increased protein expression in both groups. PhenomeExpress analysis revealed group differences in complement activation, innate immune responses and altered Wnt and TGFβ signalling, but no activation of inflammatory cytokine expression. Both groups showed suppressed circadian regulators and whereas matrix changes in Group A were chondrogenic, in Group B they were non-chondrogenic with changes in mechanoreceptors, calcium signalling, ion channels and in cytoskeletal organisers. The gene expression changes predicted 478 potential biomarkers for detection in synovial fluid to distinguish patients from the two groups.ConclusionsTwo subgroups of knee OA were identified by network analysis of RNA-Seq data with evidence for the presence of two major pathogenic pathways. This has potential importance as a new basis for the stratification of patients with OA for drug trials and for the development of new targeted treatments.

Chondroprotective Factors in Osteoarthritis: a Joint Affair

“…These add to traditional histochemistry-based approaches and offer the possibility of a new disease taxonomy. Bulk genome-wide expression analysis of chondrocytes in articular cartilage revealed two major patient subgroups, differing in complement activation, innate immune responses, and Wnt and TGFβ signaling response [ 83 •]. Single-cell sequencing has also identified cell subsets associated with both cartilage zone and level of damage [ 84 ••].…”

Decoding the genomic basis of osteoarthritis

“…To validate the 7-gene classifier, we obtained an independent gene expression dataset of low-grade cartilage samples from 60 knee osteoarthritis patients undergoing joint replacement surgery 11 . The samples had been assigned into two groups, reflecting differences in complement activation and innate immunity.…”

“…We obtained RNA expression data from low-grade cartilage tissue of 60 knee osteoarthritis patients undergoing joint replacement (27 women, 33 men, age range 63-85 years), sequenced on Illumina HiSeq 2500, with transcript quantification using kallisto and quality control as described previously 11 . We obtained gene-level data and removed batch effects as for the discovery data (Supplementary Methods).…”

Macrophage proliferation distinguishes 2 subgroups of knee osteoarthritis patients

“…However, there is a clear positive correlation between synovial inflammation and clinical features of OA, such as pain, swelling, and cartilage damage (9)(10)(11)(12)(13)(14)(15). Recently, Soul et al (16) suggested that OA patients are heterogeneous and could be stratified into 2 major patient subgroups based on the gene expression of knee articular cartilage, showing altered patterns of matrix protein gene expression (16). Indeed, clinical heterogeneity in OA pathogenesis is increasingly becoming recognized (17)(18)(19)(20).…”