Etiology of osteoarthritis: genetics and synovial joint development

Osteoarthritis (OA) has a considerable hereditary component and is considered to be a polygenic disease. Data derived from genetic analyses and genome-wide screening of individuals with this disease have revealed a surprising trend: genes associated with OA tend to be related to the process of synovial joint development. Mutations in these genes might directly cause OA. In addition, they could also determine the age at which OA becomes apparent, the joint sites involved, the severity of the disease and how rapidly it progresses. In this Review, I propose that genetic mutations associated with OA can be placed on a continuum. Early-onset OA is caused by mutations in matrix molecules often associated with chondrodysplasias, whereas less destructive structural abnormalities or mutations confer increased susceptibility to injury or malalignment that can result in middle-age onset. Finally, mutations in molecules that regulate subtle aspects of joint development and structure lead to late-onset OA. In this Review, I discuss the genetics of OA in general, but focus on the potential effect of genetic mutations associated with OA on joint structure, the role of joint structure in the development of OA--using hip abnormalities as a model--and how understanding the etiology of the disease could influence treatment.