Targeting SGK1 mitigates synovial fibrosis via suppressing M1 polarization to alleviate osteoarthritis.

BACKGROUND: Osteoarthritis (OA) is a chronic degenerative joint disorder characterized by progressive articular cartilage degradation, synovial inflammation, and pathological fibrosis. Accumulating evidence indicates that synovial pathology-particularly M1 polarization of synovial macrophages and fibrotic remodeling of the synovium-plays a critical role in OA pathogenesis. However, the precise molecular mechanisms governing these processes remain incompletely elucidated. METHODS: In this study, we established a lipopolysaccharide (LPS)-induced M1 macrophage polarization model in RAW264.7 cells and a monosodium iodoacetate (MIA)-induced rat OA model to systematically investigate the role of serum- and glucocorticoid-regulated kinase 1 (SGK1) in OA pathogenesis. RESULTS: Our findings demonstrated that SGK1 expression in synovial tissues from patients with osteoarthritis was significantly and positively correlated with the degree of M1 macrophage polarization. In vitro studies showed that SGK1 gene silencing markedly reduced the secretion of pro-inflammatory cytokines, including tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), and interleukin-6 (IL-6), in M1-polarized macrophages, and significantly attenuated the migratory and invasive capacities of fibroblast-like synoviocytes (FLS). In the MIA-induced rat osteoarthritis model, intra-articular administration of an SGK1 inhibitor significantly suppressed synovial macrophage M1 polarization and fibrotic remodeling, upregulated the expression of the cartilage-specific extracellular matrix protein type II collagen (COL2A1), and inhibited aberrant matrix metalloproteinase-13 (MMP-13) production. Furthermore, RNA sequencing analysis revealed that SGK1 predominantly regulates macrophage polarization via modulation of the Janus kinase/signal transducer and activator of transcription (JAK/STAT) signaling pathway. CONCLUSION: Collectively, these findings indicate that inhibition of SGK1 suppresses synovial macrophage M1 polarization and attenuates the progression of synovial fibrosis through modulation of the JAK/STAT signaling pathway. These results provide a novel mechanistic rationale and identify SGK1 as a potential therapeutic target for precision treatment of osteoarthritis.