Pentose phosphate pathway regulates oxidative damage and apoptosis of chondrocytes induced by fluoride

Fluorosis is a systemic disorder with primary manifestations including skeletal and dental fluorosis, where skeletal fluorosis is associated with cartilage lesions. This study investigated the pentose phosphate pathway (PPP) regulated chondrocyte apoptosis and oxidative damage induced by fluoride. Bioinformatics analysis of Gene Expression Omnibus dataset (GSE70719) showed that PPP was significantly enriched in fluorine-induced osteocytes damage. We confirmed that sodium fluoride (NaF) inhibited the PPP of chondrocytes, decreased the nicotinamide adenine dinucleotide phosphate (NADPH) and glutathione (GSH) levels, and enhanced apoptosis and oxidative injury. Moreover, NaF significantly inhibited the PPP and promoted apoptosis in rat articular cartilage. AG1, an agonist of the key enzyme glucose-6-phosphate dehydrogenase in PPP, significantly increased PPP, alleviated chondrocyte apoptosis and oxidative damage induced by NaF. These results confirmed that NaF inhibited the PPP, reduced NADPH and GSH levels, and increased oxidative stress, ultimately leading to oxidative damage and apoptosis in chondrocytes. AG1 alleviated apoptosis and oxidative damage in NaF-induced chondrocytes by activating PPP.