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

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.

Automated summary

TLR2 stimulation suppresses matrix protein expression and induces an inflammatory phenotype in chondrocytes, while also impairing mitochondrial function and reducing ATP production. The study also shows that inhibiting NOS2 can restore mitochondrial function and protect against age-related OA development.