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

被引：394

作者：

Kim, Jin-Hong ^{[1
,2
]}

Jeon, Jimin ^{[1
,2
]}

Shin, Minhee ^{[1
,2
]}

Won, Yoonkyung ^{[1
,2
]}

Lee, Minju ^{[1
,2
]}

Kwak, Ji-Sun ^{[1
,2
]}

Lee, Gyuseok ^{[1
,2
]}

Rhee, Jinseol ^{[1
,2
]}

Ryu, Je-Hwang ^{[3
,4
]}

Chun, Churl-Hong ^{[5
]}

Chun, Jang-Soo ^{[1
,2
]}

机构：

[1] Gwangju Inst Sci & Technol, Cell Dynam Res Ctr, Kwangju 500712, South Korea

[2] Gwangju Inst Sci & Technol, Sch Life Sci, Kwangju 500712, South Korea

[3] Chonnam Natl Univ, Sch Dent, Res Ctr Biomineralizat Disorders, Kwangju 500757, South Korea

[4] Chonnam Natl Univ, Sch Dent, Dent Sci Res Inst, Kwangju 500757, South Korea

[5] Wonkwang Univ, Sch Med, Dept Orthoped Surg, Iksan 570711, South Korea

来源：

CELL | 2014年 / 156卷 / 04期

基金：

新加坡国家研究基金会;

关键词：

HYPOXIA-INDUCIBLE FACTOR-2-ALPHA; FACTOR-I MTF-1; CARTILAGE DESTRUCTION; ZINC TRANSPORTER; MICE; MOUSE; IDENTIFICATION; EXPRESSION; LIVER; MODEL;

D O I：

10.1016/j.cell.2014.01.007

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

070307 [化学生物学]; 071010 [生物化学与分子生物学];

摘要：

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.

引用

页码：730 / 743

页数：14

共 35 条

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