FRI0009 Accelerated development of aging-associated and instability-induced osteoarthritis in 12/15-lipoxygenase deficient mice

L Habouri, F El Mansouri, Y Ouhaddi, J-P Pelletier, J Martel-Pelletier, M Benderdour, H Fahmi
2017 Poster Presentations   unpublished
Scientific Abstracts Friday, 16 June 2017 483 in hIL4-10FP group there was no enhanced cartilage degeneration detected compared to the PBS group (fig 3) . Conclusions: Repetitive intra-articular injection of human IL4-10FP led to antibody formation in a non-inflammatory canine model of OA. Despite the immune response, proteoglycan turnover parameters were comparable between the two treatment groups, suggesting a beneficial effect of hIL4-10FP. This study also shows that it is not evident to use
more » ... a human protein in a (canine) animal model, although this is often done. Instead, a species specific protein is warranted. Therefore a canine version of IL4-10FP will be developed to study its DMOAD activity in this model. References: [1] van Roon JA, Lafeber FP, Bijlsma JW. Synergistic activity of interleukin-4 and interleukin-10 in suppression of inflammation and joint destruction in rheumatoid arthritis. Arthritis and rheumatism. 2001;44(1):3-12. 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 PGE 2 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 PGE 2 , 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.
doi:10.1136/annrheumdis-2017-eular.6184 fatcat:rinanhnxnbbdriqlyrs6zqhewm