Fetuin-A improves knee osteoarthritis by regulating macrophage PD-1 expression to balance M1/M2 polarization

Knee osteoarthritis (KOA) features cartilage injury, synovial inflammation and abnormal mineralization. Fetuin-A exerts immunomodulatory and anti-mineralization effects, yet its role in KOA remains unclear. This study aimed to clarify whether Fetuin-A alleviates KOA and its underlying mechanism. We established destabilization of the medial meniscus (DMM)-induced KOA mouse models divided into Sham, Model, Fetuin-A, and Fetuin-A+anti-programmed cell death protein 1 (PD-1) groups. LPS-stimulated bone marrow-derived macrophage conditioned medium (BMDM-CM) system was constructed, with BMDMs grouped into Control, Model, Fetuin-A, and Fetuin-A+small interfering RNA targeting PD-1 (si-PD-1). Primary chondrocytes were incubated with corresponding CM, and we adopted micro-computed tomography, X-ray, histopathology, flow cytometry, Western blotting, ELISA and qPCR to detect joint lesions, macrophage polarization, inflammation and mineralization markers. In vivo tests showed reduced Fetuin-A in serum and synovial fluid of KOA mice, accompanied by joint stenosis, cartilage damage, M1 macrophage polarization and decreased PD-1. Fetuin-A supplementation reversed these pathological changes, while PD-1 blockade eliminated such protective effects. In vitro assays verified that Fetuin-A upregulated macrophage PD-1 to suppress M1 polarization, boost M2 polarization and lower interleukin-1β and tumor necrosis factor-α secretion. Fetuin-A-treated macrophage CM relieved chondrocyte injury, apoptosis, matrix degradation and abnormal mineralization, which was abolished by PD-1 knockdown. In summary, Fetuin-A balances M1/M2 polarization via elevating macrophage PD-1 expression, thus mitigating cartilage damage, synovitis and abnormal mineralization in KOA.