AUTHOR=Nasi Sonia , Ea Hang-Korng , So Alexander , Busso Nathalie 

TITLE=Revisiting the Role of Interleukin-1 Pathway in Osteoarthritis: Interleukin-1α and -1β, and NLRP3 Inflammasome Are Not Involved in the Pathological Features of the Murine Menisectomy Model of Osteoarthritis

JOURNAL=Frontiers in Pharmacology

VOLUME=8

YEAR=2017

URL=https://www.frontiersin.org/journals/pharmacology/articles/10.3389/fphar.2017.00282

DOI=10.3389/fphar.2017.00282

ISSN=1663-9812

ABSTRACT=<p><bold>Background:</bold> Innate immune response components such as toll-like receptors (TLRs) and NLRP3-inflammasome act in concert to increase IL-1α/β secretion by synovial macrophages. Previous results suggest that IL-1α/β could be an important mediator involved in the pathogenesis of osteoarthritis (OA).</p><p><bold>Objectives:</bold> The aim of our study was to evaluate the role of NLRP3, IL-1β, and IL-1α in the menisectomy (MNX) model of murine OA.</p><p><bold>Methods:</bold> Murine chondrocytes (CHs) and bone marrow-derived machrophages (BMDM) were stimulated with hydroxyapatite (HA) crystals, a form of calcium-containing crystal found in human OA, and IL-1β and IL-6 secretion assayed by ELISA.Conversely, the ability of IL-1β and IL-6 to induce CHs calcification was assessed <italic>in vitro</italic> by Alizarin red staining. Knees from 8 to 10 weeks old C57Bl/6J wild-type (WT) (<italic>n</italic> = 7), NLRP3<sup>−/−</sup> (<italic>n</italic> = 9), IL-1α<sup>−/−</sup> (<italic>n</italic> = 5), and IL-1β<sup>−/−</sup> (<italic>n</italic> = 5) mice were menisectomized, using the sham-operated contralateral knee as control. 8 weeks later, knee cartilage degradation and synovial inflammation were evaluated by histology. In addition, apoptotic chondrocytes, metalloproteases activity, and collagen-type 2 expression were evaluated in all mice. Joint calcification and subchondral bone parameters were quantified by CT-scan in WT and IL-1β<sup>−/−</sup> menisectomized knees.</p><p><bold>Results:</bold><italic>In vitro</italic>, HA crystals induced significant increased IL-6 secretion by CHs, while IL-1β remained undetectable.Conversely, both IL-6 and IL-1β were able to increase chondrocytes mineralization. <italic>In vivo</italic>, operated knees exhibited OA features compared to sham-operated knees as evidenced by increased cartilage degradation and synovial inflammation. In menisectomized KO mice, severity and extent of cartilage lesions were similar (IL-1α<sup>−/−</sup> mice) or exacerbated (IL-1β<sup>−/−</sup> and NLRP3<sup>−/−</sup> mice) compared to that of menisectomized WT mice. Metalloproteases activity, collagen-type 2 expression, chondrocytes apoptosis, and synovial inflammation were similar between KO and WT mice menisectomized knees. Moreover, the extent of joint calcification in osteoarthritic knees was comparable between IL-1β<sup>−/−</sup> and WT mice.</p><p><bold>Conclusions:</bold> MNX knees recapitulated features of OA, i.e, cartilage destruction, synovial inflammation, cell death, and joint calcification. Deficiency of IL-1α did not impact on the severity of these features, whereas deficiency of IL-1β or of NLRP3 led to increased cartilage erosion. Our results suggest that IL-1α and IL-1β are not key mediators in this murine OA model and may explain the inefficiency of IL-1 targeted therapies in OA.</p>