Clinical significance and implications of genetic and genomic studies in patients with osteoarthritis

Abstract

Idiopathic or primary osteoarthritis is a progressive musculoskeletal disease of diarthrodial synovial joints, whereas secondary osteoarthritis generally arises from an anteced- ent traumatic injury or abnormal synovial joint development. Presently, the medical therapy of osteoarthritis is limited, and focuses on alleviating the major clinical symptoms of osteoar- thritis, which include pain, swelling, and reduced range of joint motion. The end-stage of the osteoarthritic process often requires joint replacement surgery. Although the pathogenetic com- ponents of human osteoarthritis remain to be completely elucidated, rodent and canine models of osteoarthritis have indicated that, at least in the early stages of development, osteoarthritis involves articular chondrocyte hypermetabolism, followed by an imbalance between chondro- cyte anabolic and catabolic pathways, and limited cartilage repair. Mutations arising in several cartilage collagen isoforms, the proteoglycans aggrecan and asporin, cartilage oligomeric matrix protein, and matrilin-3 can be associated with precocious and age-related osteoarthritis, as well as chondrodysplasias. Whole genome scanning of blood cells from individuals with osteoar- thritis in Iceland, the United Kingdom, and the United States indicated the strong likelihood of osteoarthritis gene susceptibility loci on chromosome regions, 7q34-7q36.3, 11p12-11q13.4, 6p21.1-6q15, 2q31.1-2q34, and 15q21.3-15q26.1. Genetic analyses of non-extracellular matrix proteins have suggested an association of osteoarthritis with single nucleotide polymorphisms in the genes encoding growth and differentiation factor-5, secreted Frizzle-related protein-3, deiodinase-2, and calmodulin-1. The continued elucidation of genetic markers of osteoarthri- tis may one day be employed to better define, for an individual, the probability of developing osteoarthritis, the likely rate of progression of osteoarthritis, the relative risk of requiring joint arthroplasty, and predict prosthetic joint loosening.