Lessons from genetic forms of osteoarthritis for the pathogenesis of the disease

Abstract

Osteoarthritis (OA) is the most common form of arthritis (1). Although the precise etiology of the disease in most cases is unknown, it is generally accepted that OA is a multifactorial disorder involving both genetic and environmental components (2). Genetic factors are either mutations or variations in genes that result in defects or variability in cartilage matrix properties and chondrocyte metabolism. In the case of matrix defects caused by mutations in matrix genes, age-dependent cartilage degeneration may occur as a result of even normal mechanical stresses on a joint. In the case of inherited sequence variations in genes, some variations may confer increased risk for OA (3). Environmental factors include obesity, over-loading on joints, repetitive injury involving ligaments and menisci, loss of muscle strength and joint malalignment. These conditions can result in abnormal mechanical stresses on the joint, leading to cartilage degeneration. Since OA can occur as a result of one or a combination of these factors, investigating the detailed pathogenic mechanisms in all these conditions remains a formidable challenge. However, regardless of the nature of the factor(s) that initiate the disease, the pathological progression of OA follows a typical pattern (4). The earliest indication of pathological change is chondrocyte clustering as a result of increased cell proliferation and a general up-regulation of synthetic activity. Increased expression of cartilage-degrading proteinases and matrix proteins suggests an attempt at repair. Gradual loss of proteoglycans appears in the surface region of articular cartilage and this is followed by type II collagen degradation. Cracks develop along the articular surface, producing the histological image termed fibrillation. At later stages of the disease, fibrocartilage forms, probably as a consequence of unsuccessful attempts by chondrocytes to fill in the cracks. Finally, osteophytes, bony structures at the periphery of the joint surface, form.