6:2 Cl-PFESA exacerbates osteoporosis by activating the Nos2-ROS-mtDNA-STING pathway in osteoclasts: An emerging osteoporotic threat.

Epidemiological studies have suggested a link between 6:2 chlorinated polyfluoroalkyl ether sulfonate (6:2 Cl-PFESA) and skeletal disorders, but its effect on postmenopausal osteoporosis has yet to be investigated. The effects and molecular mechanisms of 6:2 Cl-PFESA on bone mineral density (BMD) of ovariectomized (OVX) mice were explored in this study. After 40 days on treatment with 6:2 Cl-PFESA, OVX mice exhibited reduced BMD and trabecular bone mass along with increased osteoclast formation. Bioinformatics analysis found that Nos2 was upregulated. Nos2 knockdown lowered the markers of osteoclasts. STRING analysis showed a strong link between Nos2 and pathways related to oxidative stress. The study observed that 6:2 Cl-PFESA elevated the expression of ROS, mtDNA, STING, and NF-ĸB. Treatment with the ROS scavenger (GSH) lowered the levels of osteoclast markers, mtDNA, STING, and NF-ĸB. Additionally, giving the STING pathway inhibitor RTA408 prevented bone loss resulting from 6:2 Cl-PFESA by blocking osteoclast activation in OVX mice.