title: Regulation of the catabolic cascade in osteoarthritis by the zinc-ZIP8-MTF1 axis.
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.
authors: Cell Dynamics Research Center and School of Life Sciences, Gwangju Institute of Science and Technology, Gwangju 500-712, Korea.
authors: Jin-Hong
authors: JH
authors: Kim
authors: Cell Dynamics Research Center and School of Life Sciences, Gwangju Institute of Science and Technology, Gwangju 500-712, Korea.
authors: Jimin
authors: J
authors: Jeon
authors: Cell Dynamics Research Center and School of Life Sciences, Gwangju Institute of Science and Technology, Gwangju 500-712, Korea.
authors: Minhee
authors: M
authors: Shin
authors: Cell Dynamics Research Center and School of Life Sciences, Gwangju Institute of Science and Technology, Gwangju 500-712, Korea.
authors: Yoonkyung
authors: Y
authors: Won
authors: Cell Dynamics Research Center and School of Life Sciences, Gwangju Institute of Science and Technology, Gwangju 500-712, Korea.
authors: Minju
authors: M
authors: Lee
authors: Cell Dynamics Research Center and School of Life Sciences, Gwangju Institute of Science and Technology, Gwangju 500-712, Korea.
authors: Ji-Sun
authors: JS
authors: Kwak
authors: Cell Dynamics Research Center and School of Life Sciences, Gwangju Institute of Science and Technology, Gwangju 500-712, Korea.
authors: Gyuseok
authors: G
authors: Lee
authors: Cell Dynamics Research Center and School of Life Sciences, Gwangju Institute of Science and Technology, Gwangju 500-712, Korea.
authors: Jinseol
authors: J
authors: Rhee
authors: Research Center for Biomineralization Disorders and Dental Science Research Institute, School of Dentistry, Chonnam National University, Gwangju 500-757, Korea.
authors: Je-Hwang
authors: JH
authors: Ryu
authors: Department of Orthopedic Surgery, Wonkwang University School of Medicine, Iksan 570-711, Korea.
authors: Churl-Hong
authors: CH
authors: Chun
authors: 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.
authors: Jang-Soo
authors: JS
authors: Chun
mesh_terms: D051722:ADAM Proteins / Q000378:metabolism; D000368:Aged; D000818:Animals; D027682:Cation Transport Proteins / Q000235:genetics / Q000378:metabolism; D019902:Chondrocytes / Q000378:metabolism / Q000473:pathology; D006801:Humans; D051741:Kruppel-Like Transcription Factors / Q000378:metabolism; D008297:Male; D020782:Matrix Metalloproteinases / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008875:Middle Aged; D010003:Osteoarthritis / Q000378:metabolism* / Q000473:pathology*; D015398:Signal Transduction; D015854:Up-Regulation; D015032:Zinc / Q000378:metabolism
chemical_list: D027682:Cation Transport Proteins; D051741:Kruppel-Like Transcription Factors; C514090:Mif1 protein, mouse; C499256:Slc39a8 protein, mouse; D051722:ADAM Proteins; D020782:Matrix Metalloproteinases; D015032:Zinc