Although osteoarthritis (OA) is the most common musculoskeletal condition that causes
significant health and social problems worldwide, its exact etiology is still unclear. With an aging and
increasingly obese population, OA is becoming even more prevalent than in previous decades. Up to
35% of the world’s population over 60 years of age suffers from symptomatic (painful, disabling) OA.
The disease poses a tremendous economic burden on the health-care system and society for diagnosis,
treatment, sick leave, rehabilitation, and early retirement. Most patients also experience sleep
disturbances, reduced capability for exercising, lifting, and walking and are less capable of working,
and maintaining an independent lifestyle. For patients, the major problem is disability, resulting
from joint tissue destruction and pain. So far, there is no therapy available that effectively arrests
structural deterioration of cartilage and bone or is able to successfully reverse any of the existing
structural defects. Here, we elucidate novel concepts and hypotheses regarding disease progression
and pathology, which are relevant for understanding underlying the molecular mechanisms as a
prerequisite for future therapeutic approaches. Emphasis is placed on topographical modeling of the
disease, the role of proteases and cytokines in OA, and the impact of the peripheral nervous system
and its neuropeptides