Background Innate immune response components such as Toll-like receptors (TLRs), NLRP3 inflammasome and the intracellular signaling molecule MyD88 are all expressed by synovial membrane and chondrocytes. Previous studies have shown that TLRs and NLRP3 inflammasome act in concert to increase IL-1β secretion by activated synovial macrophages and that IL-1β could be an important mediator involved in the pathogenesis of osteoarthritis (OA).
Objectives The aim of our study was to evaluate the role of various TLRs, NLRP3, IL1α and the signaling molecule MyD88 in a murine model of OA induced by knee menisectomy (MNX, surgical removal of the medial meniscus).
Methods Knees from 8-10 weeks old C57Bl6 wild type female (n=7), knock-out TLR-1 (n=5), -2 (n=7), -4 (n=8) -6 (n=5), NLRP3 (n=9), IL1α (n=5) or MyD88 (n=7) were menisectomized, using the sham-operated contralateral knee as a control. 8 weeks later mice were sacrificed and knee cartilage destruction evaluated by histology using the OARSI scoring method. In addition, apoptotic chondrocytes were quantified in MyD88- and NLRP3-deficient knees. Finally, synovial inflammation was also scored.
Results Operated knees exhibit OA symptoms at 8 weeks post-surgery compared to sham-operated knees as evidenced by both femoral and tibial cartilage degradation (increased OARSI score parameters, increased chondrocyte apoptosis) and by synovial inflammation. In menisectomized TLR-1, -2, -4, and -6 deficient mice, severity and extent of cartilage lesions and synovial inflammation were similar to that in MNX wild-type mice. Using the same approach, we determined that there was no significant difference in phenotype betweeen the NLRP3- or IL1α- deficient mice and wild-type control mice. Accordingly, we did not observed a significant effect of MyD88 deletion, as cartilage erosion and synovial inflammation were similar in MNX knock-out and wild-type mice.
Conclusions Knee MNX recapitulates features of OA, i.e, cartilage destruction and synovial inflammation. Deficiency of TLRs, NLRP3 inflammasome and their signalling molecule MyD88 did not impact on the severity of experimental OA. Our results suggest that NLRP3 inflammasome is either not involved in IL-1β activation or that IL-1β is not a key mediator in this murine OA model. This latter hypothesis is strengthened by the lack of efficiency of IL-1β antagonists in the treatment of OA.
Disclosure of Interest None Declared
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