Cell Dynamics Research Center and School of Life Sciences, Gwangju Institute of Science and Technology, Gwangju 500-712, Korea.
Research Center for Biomineralization Disorders and Dental Science Research Institute, School of Dentistry, Chonnam National University, Gwangju 500-757, Korea.
Cell. 2014 Feb 13;156(4):730-43. doi: 10.1016/j.cell.2014.01.007.
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.
骨关节炎（OA）主要表现为软骨退化，是由合成代谢和分解代谢因素失衡引起的。在这里，我们研究了锌（Zn2+）稳态、Zn2+转运体和 Zn(2+)-依赖性转录因子在 OA 发病机制中的作用。在 Zn2+转运体中，Zn2+ 进口器 ZIP8 在人类和小鼠的 OA 软骨中特异性上调，导致软骨细胞内的细胞内 Zn2+水平升高。ZIP8 介导的 Zn2+内流上调了软骨细胞中基质降解酶（MMP3、MMP9、MMP12、MMP13 和 ADAMTS5）的表达。ZIP8 在小鼠软骨组织中的异位表达导致 OA 软骨破坏，而 Zip8 敲除则抑制了手术诱导的 OA 发病机制，同时调节了 Zn2+内流和基质降解酶。此外，MTF1 被鉴定为介导 Zn2+/ZIP8 诱导的分解代谢因子表达的必需转录因子，而在小鼠中对 Mtf1 的遗传调节改变了 OA 发病机制。我们提出锌-ZIP8-MTF1 轴是 OA 发病机制的重要分解代谢调节剂。
