Abstract
ObjectiveNLRP3 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 methodsHuman 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.ResultsSynoviocytes 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.ConclusionsSDF-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.
Highlights
Osteoarthritis (OA) is the most common form of arthritis and a highly prevalent and disabling condition that affects movable joints, such as knees, hips, and hands (Katz et al 2021)
The expression levels of NLRP3 inflammasome (NLRP3, associated speck-like protein (ASC), and caspase-1), gasdermin D (GSDMD), and IL-1β were significantly upregulated in OA fibroblast-like synoviocytes (FLS) compared with that in healthy FLS (p < 0.05, n = 9), as estimated by western blotting (Fig. 1a)
Stromal cell-derived factor-1 (SDF-1) at a concentration of 20 ng/ml was found to increase the proliferation of OA FLS (p < 0.05, n = 6); the other two concentrations of SDF-1 used in these experiments had no significant influence on cell proliferation (p > 0.05) (Fig. 1c)
Summary
Osteoarthritis (OA) is the most common form of arthritis and a highly prevalent and disabling condition that affects movable joints, such as knees, hips, and hands (Katz et al 2021). Recent research suggests that low-grade inflammation plays an important role in the development and progression of OA (Scanzello 2017). Stromal cell-derived factor-1 (SDF-1), known as CXCL12, is a member of the homeostatic CXC family of chemokines, with emerging roles in bones, joints, and muscles (Gilbert et al 2019). Recent research has showed that SDF-1 levels increase significantly in OA synovial fluid (Kanbe et al 2002). Previous studies have speculated that SDF-1 may play a protective role in OA by inducing significant extents of osteoblast proliferation and upregulating the expression of collagen type I in OA patients (Lisignoli et al 2006; Shen et al 2014). We have previously reported that SDF-1 can increase vascular endothelial growth factor expression in chondrogenic progenitor cells (Wang et al 2017). Far, no study has been conducted to examine the effect of SDF-1 on the NLRP3 inflammasome and pyroptosis in OA or explored its underlying mechanism of action
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