Identification of the pathogenic pathways in osteoarthritic hip cartilage: commonality and discord between hip and knee OA

Abstract

Purpose: To define for the first time the transcriptome of normal and end-stage osteoarthritic (OA) hip cartilage and to identify novel pathogenic pathways involved in the disease. Methods: RNA was isolated from articular cartilage samples obtained from consented patients undergoing joint replacement surgery due to either end-stage hip OA or neck of femur fracture (NOF). Illumina HumanHT-12 V3 whole genome expression arrays were used to profile gene expressions. Raw data was analyzed and differentially expressed genes identified using the Agilent Gene Spring GX 11 package. P-values were corrected for multiple testing using the Benjamini-Hochberg method. Gene Set Enrichment Analysis (GSEA) and Ingenuity Pathway Analysis (IPA) were used to investigate functions and pathways associated with these genes, respectively. Protein interaction networks were predicted using STRING and visualized with Medusa 3.0. Differentially expressed genes were verified by real-time PCR. Results: In total we identified 1151 differentially expressed genes (fold change ≤ -1.5 or ≥1.5, P-value ≤ 0.01) between NOF (n=10) and OA hip (n=9) cartilage. Sixty canonical pathways (P-value ≤ 0.05) were identified as associated with these genes. A comparison between a published comparable knee dataset only identified 183 genes similarly differentially expressed but remarkably 35 canonical pathways overlapped between the experiments. wnt/β-catenin signalling, PI3K/AKT signalling and IL-17 signalling pathways were identified in common between both studies. Pathways such as glycosaminoglycan degradation (P-value=0.044), HIF1α signalling (P-value=0.007) and interferon signalling (P-value=0.003), were specific to our hip OA study, while IGF-1 signalling, clathrin-mediated endocytosis signalling and HMGB1 signalling were only associated with the differentially expressed genes from knee OA cartilage. Conclusions: This is the first study to report a comprehensive gene expression analysis of human hip OA cartilage compared to control (neck of femur fracture) cartilage at the whole human genome level. Our differential gene expression dataset shows excellent correlation with similar defined studies using comparable tissue but reveals discord between hip and knee OA in the behavior of individual genes although commonality with respect to the molecular pathways involved.