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Cell. 2014 Feb 13;156(4):730-43. doi: 10.1016/j.cell.2014.01.007.

Regulation of the catabolic cascade in osteoarthritis by the zinc-ZIP8-MTF1 axis.

Author information

1
Cell Dynamics Research Center and School of Life Sciences, Gwangju Institute of Science and Technology, Gwangju 500-712, Korea.
2
Research Center for Biomineralization Disorders and Dental Science Research Institute, School of Dentistry, Chonnam National University, Gwangju 500-757, Korea.
3
Department of Orthopedic Surgery, Wonkwang University School of Medicine, Iksan 570-711, Korea.
4
Cell Dynamics Research Center and School of Life Sciences, Gwangju Institute of Science and Technology, Gwangju 500-712, Korea. Electronic address: jschun@gist.ac.kr.

Abstract

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 Zn(2+)-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.

PMID:
24529376
DOI:
10.1016/j.cell.2014.01.007
[Indexed for MEDLINE]
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