Etiology of osteoarthritis: genetics and synovial joint development

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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.

Key Points

  • Genetic factors play a key part in the etiology of all subtypes of osteoarthritis (OA), including primary OA, early-onset OA with chondrodysplasia and post-traumatic OA

  • A major risk factor for OA is an imperfect joint structure—ranging from the obvious defects of hip dysplasia to subtle alterations resulting from mutation of a developmental gene

  • Participation of a gene associated with OA in the formation of an imperfect joint could occur during development and might affect the ability of mature cartilage to be repaired

  • Mutations in genes encoding different components of the same pathway could have the same influence on susceptibility to OA as each other

  • Genes associated with OA do not have to be expressed exclusively in cartilage but could also be important for the development, function or repair of bone, tendon, ligament or menisci

  • Whether genetic risk factors for OA eventually manifest as clinical disease can depend on other physical, environmental and biochemical stresses that are placed on the joint

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Figure 1: OA can be viewed as a continuum.
Figure 2: Schematic diagram of the hip joint architecture.
Figure 3: Risk factors for OA vary in their contribution to susceptibility over time.


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The author thanks J. Clohisy (Washington University School of Medicine, USA) and I. Meulenbelt (Leiden University Medical Center, The Netherlands) for their comments on the manuscript before submission; R. Todhunter (Cornell School of Veterinary Medicine, USA) for providing information prior to publication; and H. Kawaguchi (University of Tokyo Graduate School of Medicine, Japan) and C. Little (University of Sidney, Australia) for their help in producing Table 2.

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