Hexavalent chromium (Cr(VI)), an environmental hazard, can damage human organs and is associated with various diseases when ingested; however, its effects on the progression of osteoarthritis, the most prevalent form of arthritis, remain unknown. Therefore, we investigate the effects of Cr(VI) on osteoarthritis pathogenesis by evaluating the mechanistic role of a novel Cr(VI) “hot spot,” articular cartilage, using a noncarcinogenic concentration of Cr(VI) in a murine model. Intra-articular injection of 100 ppm of Cr(VI) resulted in significant cartilage degeneration; mice with surgical destabilization of the medial meniscus exposed to a low oral dose of Cr(VI) for 16 weeks also showed increased osteoarthritis parameters. Immunohistochemical analysis revealed that Cr(VI) increased osteoarthritis induc

ers, including Hif-2α and Zip8, as well as metalloproteinases Mmp3 and Mmp13. Moreover, Cr(VI)-induced Hif-2α and Zip8 promoted Mmp3 and Mmp13 expression through the NF-κB signaling pathway. Collectively, our findings suggest that Cr(VI) can influence articular cartilage degeneration and affect osteoarthritis development through the NF–κB–Hif-2α/Zip8 signaling pathway.