Synovial fluid cytokine concentrations as possible prognostic indicators in the ACL-deficient knee

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Abstract
Approximately 44% of patients develop osteoarthritis (OA) following rupture of the anterior cruciate ligament (ACL) if the injury is left unrepaired. Restoring knee stability through reconstruction, while providing symptomatic relief, has not been shown to reduce the incidence of degenerative changes. In fact, recent studies have shown that 50%–60% of ACL-reconstructed patients go on to develop degenerative changes or frank osteo-arthritis. In light of these data, our group suggests that the cause of post-traumatic osteoarthritis is not biomechanical but biochemical. To test this hypothesis, we measured levels of nine cytokines which are important in modulating physiological and pathophysiological metabolism of cartilage in knee joint synovial fluid following ACL rupture. Our patient population contained both acute und chronic ACL ruptures. A total of 84 samples were collected and analyzed by enzyme-linked immunosorbent assay. On the basis of the data collected, we were able to identify subgroups of patients who, on the basis of their synovial fluid cytokine profile, may be at greater or leasser risk of developing post-traumatic OA. In general, patients displayed concentrations of interleukin-1α (IL-1α), basic fibroblastic growth factor (bFGF), transforming growth factor-β (TGF-β), granulocyte/macrophage-colony stimulating factor (GM-CSF), IL-6, and IL-8 that we interpreted as being consistent with an inflammatory reaction. Of great interest is the fact that the levels of these cytokines were very similar in patients 4 weeks after injury and in chronic patients, leading us to hypothesize that a chronic smoldering inflammatory reaction persists after resolution of the acute effusion. This chronic inflammatory reaction could be the cause of cartilage degeneration seen in patients after ACL reconstruction. Furthermore, this study identified two distinct subpopulations of patients with dramatically differing levels of IL-1β and TNF-α in their synovial fluids. IL-1β and TNF-α were either high acutely and decreased to moderate levels over time, or they were zero acutely and remained zero or low. This is likely to be a very important observation as these two cytokines are key components of the inflammatory response and are the main intra-articular cytokines that provoke cartilage loss. It is our hypothesis that the group with high levels of IL-1β and TNF-α contains the 50%–60% of the patient population which goes on to develop OA, despite knee stabilization with ACL reconstruction. Conversely, we suggest that the group whose synovial fluid contains no IL-1β or TNF-α is protected from developing OA post-traumatically. IL-1-receptor antagonist protein (IRAP), the cytokine that antagonizes the biological effects of IL-1, was present acutely in our patient population; however, it was undetectable in chronic ACL-deficient knees. These data suggest the loss with time of an important cartilage-protective cytokine. The lack of IRAP chronically may allow IL-1β to act in an unrestrained manner resulting in cartilage loss. In addition, IL-1β promotes the secretion of many other inflammatory cytokines which may result in the chronic smoldering inflammatory reaction referred to above. These data encourage further study of the evaluation of cytokine concentrations in the ACL-deficient joint as a means of obtaining both prognostic and mechanistic information of clinical value to the physician.

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