Purpose of review: This review addresses possible common mechanisms of how recently identified consistent osteoarthritis susceptibility genes influence both the onset of osteoarthritis and its progression towards clinical outcomes.
Recent findings: Genetic association studies have identified a few consistent osteoarthritis susceptibility genes (FRZB, GDF5, and DIO2) that replicate across different populations. Remarkably, each of these genes appears to be primarily involved in the endochondral ossification processes.
Summary: We hypothesize that these osteoarthritis susceptibility genes may play a dual negative role. In early developmental processes, they may involve aberrant skeletal morphogenesis leading to either malformation of joints or aberrant bone composition or both, thereby increasing the biomechanical burden on the articular cartilage surface. Later in life in articular cartilage, these genes may affect the propensity of articular chondrocytes to become hypertrophic. As hypertrophic chondrocytes are not able to maintain cartilage homeostasis, these genes may, in part, be responsible for both the onset of osteoarthritis and the progression towards clinical outcomes. Major therapeutic advances may come from a focus on factors that enhance phenotypic stability of the articular chondrocyte during life, promoting the healthy articular cartilage.