NOS inhibition reverses TLR2-induced chondrocyte dysfunction and attenuates age-related osteoarthritis.
Ping ShenSebastian ServePeihua WuXiaohui LiuYujie DaiNayar Durán-HernándezDan Thi Mai NguyenMichael FuchsTazio MaleitzkeMarie-Jacqueline ReisenerMaria DzamukovaKatrin NussbaumerTobias M BrunnerYonghai LiVivien HolecskaGitta Anne HeinzFrederik R HeinrichPawel DurekEleftheria ZegginiClemens GwinnerTobias JungEleftheria ZegginiTobias WinklerMir-Farzin MashreghiMatthias PumbergerCarsten F PerkaMax LöhningPublished in: Proceedings of the National Academy of Sciences of the United States of America (2023)
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.
Keyphrases
- nitric oxide synthase
- knee osteoarthritis
- toll like receptor
- nitric oxide
- inflammatory response
- poor prognosis
- immune response
- endothelial cells
- chronic pain
- high glucose
- oxidative stress
- single cell
- rheumatoid arthritis
- diabetic rats
- nuclear factor
- signaling pathway
- binding protein
- spinal cord injury
- induced pluripotent stem cells
- risk assessment
- extracellular matrix
- genome wide
- cell death
- drug induced
- physical activity
- pluripotent stem cells
- type diabetes
- bioinformatics analysis
- reactive oxygen species
- epithelial mesenchymal transition