Regulation of the Catabolic Cascade in Osteoarthritis by the Zinc-ZIP8-MTF1 Axis

Osteoarthritis (OA), primarily characterized by cartilage degeneration, is caused by an imbalance between anabolic and catabolic factors. Here, we investigated the role of zinc (Zn2+) homeostasis, Zn2+ transporters, and Zn2+-dependent transcription factors in OA pathogenesis. Among Zn2+ transporters, the Zn2+ importer ZIP8 was specifically upregulated in OA cartilage of humans and mice, resulting in increased levels of intracellular Zn2+ in chondrocytes. ZIP8-mediated Zn2+ influx upregulated the expression of matrix-degrading enzymes (MMP3, MMP9, MMP12, MMP13, and ADAMTS5) in chondrocytes. Ectopic expression of ZIP8 in mouse cartilage tissue caused OA cartilage destruction, whereas Zip8 knockout suppressed surgically induced OA pathogenesis, with concomitant modulation of Zn2+ influx and matrix-degrading enzymes. Furthermore, MTF1 was identified as an essential transcription factor in mediating Zn2+/ZIP8-induced catabolic factor expression, and genetic modulation of Mtf1 in mice altered OA pathogenesis. We propose that the zinc-ZIP8-MTF1 axis is an essential catabolic regulator of OA pathogenesis. [Display omitted] •Zinc importer ZIP8 is upregulated in osteoarthritic cartilage of human and mice•ZIP8-mediated zinc influx activates MTF1 transcription factor•Genetic modulation of Zip8 and Mtf1 in mice alters OA pathogenesis•Zinc·ZIP8·MTF1 axis regulates catabolic factor expression and OA pathogenesis Upregulated zinc importer ZIP8 in osteoarthritic cartilage causes cellular Zn2+ influx and MTF1 activation in chondrocytes, which, together, drive catabolic factor expression and osteoarthritis cartilage destruction.