Inflammation in joint injury and post-traumatic osteoarthritis

Abstract

Inflammation is a variable feature of osteoarthritis (OA), associated with joint symptoms and progression of disease. Signs of inflammation can be observed in joint fluids and tissues from patients with joint injuries at risk for development of post-traumatic osteoarthritis (PTOA). Furthermore, inflammatory mechanisms are hypothesized to contribute to the risk of OA development and progression after injury. Animal models of PTOA have been instrumental in understanding factors and mechanisms involved in chronic progressive cartilage degradation observed after a predisposing injury. Specific aspects of inflammation observed in humans, including cytokine and chemokine production, synovial reaction, cellular infiltration and inflammatory pathway activation, are also observed in models of PTOA. Many of these models are now being utilized to understand the impact of post-injury inflammatory response on PTOA development and progression, including risk of progressive cartilage degeneration and development of chronic symptoms post-injury. As evidenced from these models, a vigorous inflammatory response occurs very early after joint injury but is then sustained at a lower level at the later phases. This early inflammatory response contributes to the development of PTOA features including cartilage erosion and is potentially modifiable, but specific mediators may also play a role in tissue repair. Although the optimal approach and timing of anti-inflammatory interventions after joint injury are yet to be determined, this body of work should provide hope for the future of disease modification tin PTOA.

Keywords: Chemokines; Cytokines; Inflammation; Joint injury; Osteoarthritis; Post-traumatic arthritis.

Figure 1. Perpetuation of Inflammation as a mechanism leading to PTOA

Joint injury sets off a robust acute inflammatory response that includes production of both pro- and anti-inflammatory cytokines, molecular “danger” signals such as the S100A family of proteins, activation of the complement cascade. In certain individuals the influence of anti-inflammatory factors (i.e. IL-10 and IL-1RA) produced in the early post-injury period may allow for resolution of inflammation and reduce the risk of progressing to PTOA. However, perpetuation of inflammation via continued activation of innate inflammatory pathways may promote progression to PTOA in the injured joint. A number of factors may lead to perpetuation of inflammation after joint injury. These include the severity of the initial injury, the balance of pro- and anti-inflammatory factors produced in the acute and subacute post-injury periods, and repeated macro- or micro- injury which can promote continuous cycles of inflammatory activation involving innate pathways such as the complement cascade and danger-signal mediated pathways. Anti-inflammatory approaches (i.e. intraarticular IL-1Ra) to interfere with the acute phase (dashed red line) are already being tested in animal models and hold promise for prevention of PTOA. Whether resolution of chronic inflammation (dashed red arrow) can be accomplished to slow progression of structural change and chronic disability remains to be determined.