Osteoarthritis and cartilage · 2026
Interplay between canonical Wnt signaling and α5β1 integrins modulates mechanoresponse in human articular cartilage.
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Viudes-Sarrión N, Castro-Viñuelas R, Vaes N, Blain E J, Lories R J, Jonkers I
Аннотация
OBJECTIVES: Mechanical cues are essential for cartilage homeostasis, yet their interaction with molecular pathways dysregulated in osteoarthritis (OA) remains poorly understood. Canonical Wnt signalling regulates cartilage biology and cell-matrix interactions, but its role in integrin-dependent mechanoregulation is unclear. This study investigated how Wnt activation affects chondrocyte responses to physiological mechanical loading, focusing on α5β1 integrin and cytoskeletal organisation.
METHODS: Human cartilage explants from non-OA and OA donors were subjected to short-term physiological cyclic compression. Canonical Wnt signalling was activated with CHIR99021, and α5β1 integrins were blocked with ATN-161 during loading. Chondrocyte responses were assessed by mechanoresponsive and matrix-related gene expression, α5β1 complex formation using proximity ligation assay, and F-actin organisation by confocal microscopy.
RESULTS: OA chondrocytes exhibited increased ITGA5 and ITGB1 but reduced ITGA10 expression. In non-OA cartilage, Wnt activation increased ITGB1 expression and α5β1 complex formation, while loading further enhanced ITGA5 and ITGB1 transcription under Wnt-activated conditions. Under control conditions, loading induced mechanoresponsive and anabolic gene expression, whereas these responses were attenuated by Wnt activation and partially restored by α5β1 blockade. Mechanical loading promoted cortical F-actin reorganisation across cartilage zones irrespective of disease status or treatment. Wnt activation did not induce distinct cytoskeletal phenotypes under loading, and load-induced actin remodelling remained comparable between groups.
CONCLUSIONS: These findings identify α5β1 integrin as a key mediator of Wnt-driven chondrocyte mechanoresponsiveness. Although loading consistently promoted cortical F-actin reorganisation, Wnt-associated changes in load responsiveness were primarily mediated through integrin-dependent mechanisms rather than major alterations in actin organisation, highlighting integrin signalling as a potential therapeutic target in OA.
METHODS: Human cartilage explants from non-OA and OA donors were subjected to short-term physiological cyclic compression. Canonical Wnt signalling was activated with CHIR99021, and α5β1 integrins were blocked with ATN-161 during loading. Chondrocyte responses were assessed by mechanoresponsive and matrix-related gene expression, α5β1 complex formation using proximity ligation assay, and F-actin organisation by confocal microscopy.
RESULTS: OA chondrocytes exhibited increased ITGA5 and ITGB1 but reduced ITGA10 expression. In non-OA cartilage, Wnt activation increased ITGB1 expression and α5β1 complex formation, while loading further enhanced ITGA5 and ITGB1 transcription under Wnt-activated conditions. Under control conditions, loading induced mechanoresponsive and anabolic gene expression, whereas these responses were attenuated by Wnt activation and partially restored by α5β1 blockade. Mechanical loading promoted cortical F-actin reorganisation across cartilage zones irrespective of disease status or treatment. Wnt activation did not induce distinct cytoskeletal phenotypes under loading, and load-induced actin remodelling remained comparable between groups.
CONCLUSIONS: These findings identify α5β1 integrin as a key mediator of Wnt-driven chondrocyte mechanoresponsiveness. Although loading consistently promoted cortical F-actin reorganisation, Wnt-associated changes in load responsiveness were primarily mediated through integrin-dependent mechanisms rather than major alterations in actin organisation, highlighting integrin signalling as a potential therapeutic target in OA.