Background/Purpose:

12/15-Lipoxygenase (12/15-LOX) catalyzes the generation of various anti-inflammatory lipid mediators, and has been implicated in several inflammatory and degenerative diseases. However, there is currently no evidence that 12/15-LOX has a role in osteoarthritis (OA). The aim of this study was to investigate the role of 12/15-LOX in the pathogenesis of OA.

Methods:

The development of aging-associated and destabilization of the medial meniscus (DMM)-induced OA were compared in 12/15-LOX-deficient (12/15-LOX-/-) and wild-type (WT) mice. The extent of cartilage damage was evaluated by histology. The expression of OA markers was evaluated by immunohistochemistry and RT-PCR. Cartilage explants were stimulated with IL-1α in the absence or presence of the 12/15-LOX metabolites, 15-HETE, 13-HODE or LXA4, and the levels of MMP-13, NO and PGE₂ were determined. The effect of LXA4 on the progression of OA was evaluated in WT mice.

Results:

The expression of 12/15-LOX in cartilage increased during the progression of DMM-induced OA and with aging in WT mice. Cartilage degeneration was more severe in 12/15-LOX-/- mice compared to WT mice in both models of OA, and this was associated with increased expression of MMP-13, ADAMTS5, iNOS, and mPGES-1. Treatment of cartilage explants with 12/15-LOX metabolites, suppressed IL-1α-induced production of MMP-13, NO and PGE₂, with LXA4 being the most potent. Intra-peritoneal injection of LXA4 reduced the severity of DMM-induced cartilage degradation.

Conclusion:

These data suggest an important role of 12/15-LOX in the pathogenesis of OA. They also suggest that activation of this pathway may provide a novel strategy for prevention and treatment of OA.

« Back to 2017 ACR/ARHP Annual Meeting

ACR Meeting Abstracts - https://acrabstracts.org/abstract/accelerated-development-of-aging-associated-and-instability-induced-osteoarthritis-in-1215-lipoxygenase-deficient-mice/