Objective: NLRP3 inflammasome may play a key role in OA pathogenesis. Stromal cell-derived factor-1 (SDF-1) is a homeostatic CXC chemokine. Since the role of SDF-1 in OA has not been explored, this study aimed to examine the effect of SDF-1 on NLRP3 inflammasome and pyroptosis in synoviocytes from OA joints.
Materials and methods: Human synovium was obtained from OA patients for isolation of primary synoviocytes and a murine model of collagenase-induced OA was established for testing intra-articular injections of SDF-1. Immunoblotting assays were used to examine the effects and underlying mechanism of action of SDF-1 on NLRP3 inflammasome and synoviocyte pyroptosis in synoviocytes. Inhibitors of AMPK and PI3K-mTOR were utilized to investigate the key signaling pathways involved in SDF-1-mediated OA inflammasome formation and pyroptosis.
Results: Synoviocytes from OA joints exhibited significantly higher expression of NLRP3 inflammasome and biomarkers of synoviocyte pyroptosis relative to healthy individuals. This was confirmed in the collagenase-induced OA model, where OA synoviocytes had a significantly lower SDF-1 expression than healthy ones. SDF-1 treatment in synoviocytes of OA patients and collagenase-induced OA led to significant downregulation in the expression of NLRP3 inflammasome and synoviocyte pyroptosis biomarkers. Inhibition of the AMPK signaling pathway significantly suppressed the inhibitory effect of SDF-1 on NLRP3 inflammasome expression of OA synoviocytes. However, blocking the SDF-1-activated PI3K-mTOR signaling pathway could still suppress the expression of NLRP3 inflammasome and synoviocyte pyroptosis biomarkers.
Conclusions: SDF-1 ameliorates NLRP3 inflammasome and pyroptosis in OA synoviocytes through activation of the AMPK signaling pathway. Therefore, SDF-1 may be a novel therapeutic target for OA.
Keywords: Low-grade inflammation; NLRP3 inflammasome; Osteoarthritis (OA); Pyroptosis; Stromal cell-derived factor-1; Synoviocyte; Synovitis.