Targeting SGK1 Mitigates Synovial Fibrosis via Suppressing M1 Polarization to Alleviate Osteoarthritis

Synovial inflammation and fibrosis constitute significant pathological characteristics of osteoarthritis, with their progression being intricately linked to the M1 polarization of synovial macrophages and subsequent synovial fibrosis. Despite this understanding, the precise molecular mechanisms remain elusive. In the present study, we employed both a lipopolysaccharide (LPS)-induced inflammation model and an anterior cruciate ligament transection (ACLT)-induced osteoarthritis rat model to elucidate the role of serum and glucocorticoid-regulated kinase 1 (SGK1) in this context. RNA sequencing analysis revealed that the knockdown of SGK1 markedly suppressed the activity of the JAK-STAT signaling pathway in macrophages. Furthermore, in vitro experiments demonstrated that the silencing of SGK1 led to a reduction in the release of pro-inflammatory cytokines, such as TNF-α, IL-1β and IL-6, and diminished the migratory and invasive capabilities of fibroblast-like synoviocytes (FLS). Mechanistically, the silencing of SGK1 was found to inhibit the expression of M1 polarization markers, specifically iNOS and CD86, by suppressing JAK1-STAT3 phosphorylation. In an ACLT-induced osteoarthritis (OA) rat model, intra-articular administration of an SGK1 inhibitor significantly attenuated synovitis and fibrosis. Histological analyses revealed an up-regulation of collagen II expression and a down-regulation of MMP13, indicating a chondroprotective effect. Collectively, these findings suggest that SGK1 modulates macrophage M1 polarization and synovial fibrosis via the JAK1-STAT3 signaling pathway, and that targeted inhibition of SGK1 may represent a novel therapeutic strategy for OA management. This study thus provides a theoretical foundation for the development of anti-OA pharmacological interventions targeting SGK1.