Article Text

FRI0009 Accelerated development of aging-associated and instability-induced osteoarthritis in 12/15-lipoxygenase deficient mice
  1. L Habouri,
  2. F El Mansouri,
  3. Y Ouhaddi,
  4. J-P Pelletier,
  5. J Martel-Pelletier,
  6. M Benderdour,
  7. H Fahmi
  1. Medicine, CRCHUM, Montreal, Canada


Background 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).

Objectives 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.

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

Acknowledgements This work was supported by the Canadian Institutes of Health Research (CIHR) Grant MOP-130293, the Arthritis Society, and the Fonds de la Recherche du Centre de Recherche du Centre Hospitalier de l'Université de Montréal (CRCHUM).

Disclosure of Interest None declared

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