Ping Shen, Sebastian Serve, Peihua Wu, Xiaohui Liu, Yujie Dai, Nayar Durán-Hernández, Dan Thi Mai Nguyen, Michael Fuchs, Tazio Maleitzke, Marie-Jacqueline Reisener, Maria Dzamukova, Katrin Nussbaumer, Tobias M. Brunner, Yonghai Li, Vivien Holecska, Gitta A. Heinz, Frederik Heinrich, Pawel Durek, Georgia Katsoula, Clemens Gwinner, Tobias Jung, Eleftheria Zeggini, Tobias Winkler, Mir-Farzin Mashreghi, Matthias Pumberger, Carsten Perka, Max Löhning

NOS inhibition reverses TLR2-induced chondrocyte dysfunction and attenuates age-related osteoarthritis

  • Multidisciplinary
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Osteoarthritis (OA) is a joint disease featuring cartilage breakdown and chronic pain. Although age and joint trauma are prominently associated with OA occurrence, the trigger and signaling pathways propagating their pathogenic aspects are ill defined. Following long-term catabolic activity and traumatic cartilage breakdown, debris accumulates and can trigger Toll-like receptors (TLRs). Here we show that TLR2 stimulation suppressed the expression of matrix proteins and induced an inflammatory phenotype in human chondrocytes. Further, TLR2 stimulation impaired chondrocyte mitochondrial function, resulting in severely reduced adenosine triphosphate (ATP) production. RNA-sequencing analysis revealed that TLR2 stimulation upregulated nitric oxide synthase 2 ( NOS2 ) expression and downregulated mitochondria function-associated genes. NOS inhibition partially restored the expression of these genes, and rescued mitochondrial function and ATP production. Correspondingly, Nos2 −/− mice were protected from age-related OA development. Taken together, the TLR2–NOS axis promotes human chondrocyte dysfunction and murine OA development, and targeted interventions may provide therapeutic and preventive approaches in OA.

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