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

Authors

Le Cao, Guohui Liu, Haitao Yang, Wenbin Wu, Ran Zeng

Published in

Biochemical pharmacology. Pages 118411. Aug 29, 2026. Epub Aug 29, 2026.

Abstract

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.

PMID:
42667963
Bibliographic data and abstract were imported from PubMed on 30 Aug 2026.

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