Aging theories of primary osteoarthritis: from epidemiology to molecular biology

Osteoarthritis is the most common disabling condition of humans in the western world. It has been known for a very long time that aging is the most prominent risk factor for the initiation and progression of the disease, but the explanations for this phenomenon have changed over time. The most longstanding theory is that osteoarthritis develops because of continuous mechanical wear and tear. However, osteoarthritis can also be the result of time/age-related modifications to cartilage matrix components. One of the simplest biological explanations for the initiation and progression of osteoarthritic cartilage degeneration is a mere loss of viable cells, due to apoptosis or other mechanisms. Overall, the most likely scenario is that the cells and the matrix of articular cartilage get older over time, and eventually the tissue enters a senescence-like state that makes it more prone to enter the osteoarthritic degeneration pathway. Thus, patients with osteoarthritis might progress more quickly to the senescence phenotype compared to others. Moreover, stressful conditions associated with the osteoarthritic disease process might further promote chondrocyte senescence. Primary osteoarthritis in this model would be a "premature" degeneration of the joint due to a premature chondrocyte senescence. By analogy to neurodegenerative disorders, one could refer to osteoarthritis as the "M. Alzheimer" of articular cartilage. One of the most important implications of this hypothesis is that it points to issues of cellular degeneration as the basis for understanding the initiation and progression of osteoarthritis. Equally important, it emphasizes that whatever treatment we envisage for osteoarthritis, we must take into account that we are dealing with aged/(pre)senescent cells that no longer have the ability of their juvenile counterparts to counteract the many mechanical, inflammatory, and/or other assaults to the tissue.