Pathogenetic mechanisms of posttraumatic osteoarthritis: opportunities for early intervention

Abstract

Osteoarthritis (OA) is characterized by joint pain and stiffness with radiographic evidence of joint space narrowing, osteophytes, and subchondral bone sclerosis. Posttraumatic OA (PTOA) arises from joint trauma, which accounts for a fraction of all patients with OA. Articular cartilage breakdown can occur soon or for years after a joint injury. Even with the current care of joint injuries, such as anatomic reduction and rigid fixation of intra-articular fractures and reconstruction of ruptured ligaments with successful restoration of joint biomechanics, the risk of PTOA after joint injuries ranges from 20% to more than 50%. The time course for the progression of PTOA is highly variable and risk of PTOA increases with patient age at the time of joint injury, suggesting that biologic factors may be involved in the progression of PTOA. Therapeutic options are limited due largely to the lack of information on the mechanisms underlying the progression of PTOA. This review summarizes the current studies on the pathogenetic mechanisms of PTOA, with a main focus on the metabolic changes in articular cartilage in the acute posttraumatic phase and the early chronic phase, a clinically asymptomatic period. Recent studies have revealed that mechanical damage to the articular tissues may lead to changes in gene expression and cartilage metabolism, which could trigger a cascade of events leading to degradation of articular cartilage and pathologic changes in other joint tissues. Understanding the mechanobiologic, molecular and cellular changes that lead to continued cartilage degradation in the relatively early phases after joint injury may open up new opportunities for early clinical intervention.

Keywords: Osteoarthritis; articular cartilage; joint injury; ligament; meniscus; posttraumatic osteoarthritis.

Figure 1

Abnormal loading activates chondrocyte mechanoreceptors and catabolic pathways, leading to articular cartilage degradation through a mechanoreceptor-MMP-ECM breakdown cycle.

Figure 2

Possible pathogenetic mechanisms underlying the development of PTOA after joint injury. Although the initial pathological changes may vary depending on the damage to specific joint tissues, these changes eventually lead to articular cartilage degradation and joint destruction. The synovium and articular cartilage may interact with each other through specific mediators in synovial fluid, which are secreted by either chondrocytes or synoviocytes.

Figure 3

Potential opportunities for early biologic/ pharmacologic interventions to prevent or halt the progression of PTOA. The therapeutic strategies proposed here emphasize the importance of early intervention by a combination of upstream targets (e.g., Nfatl and Runx2 inhibitors), caspase inhibitors, and anti-oxidants to block chondrocyte dysfunction, synoviocyte dysfunction, and chondrocyte apoptosis at the early stage of PTOA.