Widespread epigenomic, transcriptomic and proteomic differences between hip osteophytic and articular chondrocytes in osteoarthritis

• Published in: Rheumatology (Oxford, England) England), 2018-08, Vol.57 (8), p.1481-1489
• Main Authors: Steinberg, Julia, Brooks, Roger A, Southam, Lorraine, Bhatnagar, Sahir, Roumeliotis, Theodoros I, Hatzikotoulas, Konstantinos, Zengini, Eleni, Wilkinson, J Mark, Choudhary, Jyoti S, McCaskie, Andrew W, Zeggini, Eleftheria
• Format: Article
• Language: English
• Subjects: Adult; Aged; Aged, 80 and over; Basic and Translational Science; Cartilage (articular); Cartilage diseases; Cartilage oligomeric matrix protein; Cartilage, Articular - metabolism; Cartilage, Articular - pathology; Chondrocytes; Chondrocytes - metabolism; Chondrocytes - pathology; Chromatography, Liquid; DNA Methylation; DNA sequencing; Epigenomics - methods; Extracellular matrix; Female; Genetic diversity; Genome-wide association studies; Genome-Wide Association Study; Genomes; Hip; Humans; Male; Mass Spectrometry; Matrix protein; Middle Aged; Osteoarthritis; Osteoarthritis, Hip - genetics; Osteoarthritis, Hip - metabolism; Osteoarthritis, Hip - pathology; Osteophytes; Platelet aggregation; Proteomics; Proteomics - methods; Ribonucleic acid; RNA; RNA - genetics; Surgery
• ISSN: 1462-0324; 1462-0332
• DOI: 10.1093/rheumatology/key101

Abstract Objectives To identify molecular differences between chondrocytes from osteophytic and articular cartilage tissue from OA patients. Methods We investigated genes and pathways by combining genome-wide DNA methylation, RNA sequencing and quantitative proteomics in isolated primary chondrocytes from the cartilaginous layer of osteophytes and matched areas of low- and high-grade articular cartilage across nine patients with OA undergoing hip replacement surgery. Results Chondrocytes from osteophytic cartilage showed widespread differences to low-grade articular cartilage chondrocytes. These differences were similar to, but more pronounced than, differences between chondrocytes from osteophytic and high-grade articular cartilage, and more pronounced than differences between high- and low-grade articular cartilage. We identified 56 genes with significant differences between osteophytic chondrocytes and low-grade articular cartilage chondrocytes on all three omics levels. Several of these genes have known roles in OA, including ALDH1A2 and cartilage oligomeric matrix protein, which have functional genetic variants associated with OA from genome-wide association studies. An integrative gene ontology enrichment analysis showed that differences between osteophytic and low-grade articular cartilage chondrocytes are associated with extracellular matrix organization, skeletal system development, platelet aggregation and regulation of ERK1 and ERK2 cascade. Conclusion We present a first comprehensive view of the molecular landscape of chondrocytes from osteophytic cartilage as compared with articular cartilage chondrocytes from the same joints in OA. We found robust changes at genes relevant to chondrocyte function, providing insight into biological processes involved in osteophyte development and thus OA progression.