5-lipoxygenase is critically involved in joint inflammation and damage in experimental osteoarthritis

To investigate the role of 5-lipoxygenase (5-Lox) in driving joint inflammation and damage in a model of osteoarthritis induced by collagenase in mice.

An osteoarthritis model was established in adult SV129 wild-type (WT) and 5-Lox-deficient (5-Lox^-/-) mice by intra-articular injection of collagenase VII into the tibiofemoral cavity on days 1 and 3. A group of WT mice injected with collagenase was treated with zileuton, an inhibitor of 5-Lox. At different time points after collagenase injection, the expression of 5-Lox and metalloproteinases was assessed using immunohistochemistry and PCR, respectively. Histopathological markers of tissue inflammation and damage were analyzed in whole tissue by HE and safranin O/fast green staining.

The injection of collagenase increased the protein expression of 5-Lox at 7-21 days after this challenge, returning to the basal level on day 42. The expression of Lta4-hydrolase, a critical enzyme involved in leukotriene B4 production, also increased with time after collagenase injection. Compared with WT mice, 5-Lox^-/- mice presented less inflammation, including reduced cell infiltration and synovial hyperplasia, at 42 days after collagenase insult. Furthermore, 5-Lox^-/- mice also presented reduced cartilage degradation and lower expression of metalloproteinases 3 and 13 in affected joints. Interestingly, all the inflammatory parameters and degree of cartilage damage improved in the mice treated with zileuton when the compound was given 21 days after collagenase injection.

5-Lox is critical for joint inflammation and degradation in a mouse model of osteoarthritis. Inhibiting 5-Lox with Zileuton effectively prevented joint damage and inflammation, even when it was given weeks after the inciting stimulus, suggesting that it is a potential strategy to limit the progression of osteoarthritis.