Cell Dynamics Research Center, School of Life Sciences, Gwangju Institute of Science and Technology, Gwangju, Korea.
Nat Med. 2010 Jun;16(6):687-93. doi: 10.1038/nm.2153. Epub 2010 May 23.
Osteoarthritic cartilage destruction is caused by an imbalance between anabolic and catabolic factors. Here, we show that hypoxia-inducible factor-2alpha (HIF-2alpha, encoded by EPAS1) is a catabolic transcription factor in the osteoarthritic process. HIF-2alpha directly induces the expression in chondrocytes of genes encoding catabolic factors, including matrix metalloproteinases (MMP1, MMP3, MMP9, MMP12 and MMP13), aggrecanase-1 (ADAMTS4), nitric oxide synthase-2 (NOS2) and prostaglandin-endoperoxide synthase-2 (PTGS2). HIF-2alpha expression was markedly increased in human and mouse osteoarthritic cartilage, and its ectopic expression triggered articular cartilage destruction in mice and rabbits. Moreover, mice transgenic for Epas1 only in chondrocytes showed spontaneous cartilage destruction, whereas heterozygous genetic deletion of Epas1 in mice suppressed cartilage destruction caused by destabilization of the medial meniscus (DMM) or collagenase injection, with concomitant modulation of catabolic factors. Our results collectively demonstrate that HIF-2alpha causes cartilage destruction by regulating crucial catabolic genes.
骨关节炎软骨破坏是由合成代谢和分解代谢因素之间的失衡引起的。在这里,我们表明缺氧诱导因子-2α(HIF-2α,由 EPAS1 编码)是骨关节炎过程中的一种分解代谢转录因子。HIF-2α 直接诱导软骨细胞中编码分解代谢因子的基因的表达,包括基质金属蛋白酶(MMP1、MMP3、MMP9、MMP12 和 MMP13)、聚集蛋白酶-1(ADAMTS4)、一氧化氮合酶-2(NOS2)和前列腺素内过氧化物合酶-2(PTGS2)。HIF-2α 的表达在人类和小鼠骨关节炎软骨中明显增加,其异位表达在小鼠和兔中引发关节软骨破坏。此外,软骨细胞中仅表达 Epas1 的转基因小鼠表现出自发性软骨破坏,而在小鼠中杂合性遗传缺失 Epas1 可抑制由内侧半月板不稳定(DMM)或胶原酶注射引起的软骨破坏,同时调节分解代谢因子。我们的研究结果表明,HIF-2α 通过调节关键的分解代谢基因导致软骨破坏。