Bone & Cartilage Regenerative Medicine, Faculty of Medicine, University of Tokyo, Tokyo 113-8655, Japan.
Osteoarthritis Cartilage. 2010 Dec;18(12):1552-6. doi: 10.1016/j.joca.2010.10.006. Epub 2010 Oct 13.
Endochondral ossification, a conversion process from nonvascularized and hypoxic cartilage to highly vascularized bone, plays a crucial role in osteoarthritis (OA) development as well as in physiological skeletal growth. We have shown that hypoxia-inducible factor-2α (HIF-2α, encoded by EPAS1) is an extensive regulator of the endochondal ossification process. Here we review the possible signaling network regulating OA development on the axis of HIF-2α.
Peer reviewed publications published prior to August 2010 were searched in the Pubmed database. Articles that were relevant to HIF and molecular mechanisms of the endochondral ossification and OA were selected.
As a trigger of OA, mechanical stress may induce the upstream NF-κB signal and HIF-2α expression in joint cartilage of mice and humans, which causes transactivation of endochondral ossification-related molecules with the most potent β-subunit partner aryl hydrocarbon nuclear translocator-like (ARNTL). In contrast to HIF-2α, HIF-1α functions to maintain cartilage via a distinct mechanism, so that the shifting of the HIFs might possibly be involved in an OA pathogenesis.
Signals on the HIF-2α axis from NF-κB signaling to the endochondral ossification-related molecules, possibly in combination with HIF-2α and ARNTL, may represent a rational therapeutic target for OA with minimal effects on physiological skeletal homeostasis.
软骨内骨化是一种将非血管化和缺氧软骨转化为高度血管化骨的过程，在骨关节炎（OA）的发展以及生理骨骼生长中起着至关重要的作用。我们已经表明，缺氧诱导因子-2α（HIF-2α，由 EPAS1 编码）是软骨内骨化过程的广泛调节因子。在这里，我们综述了调节 OA 发展的可能信号网络，其轴位于 HIF-2α。
在 Pubmed 数据库中搜索了截至 2010 年 8 月之前发表的同行评审出版物。选择了与 HIF 和软骨内骨化和 OA 的分子机制相关的文章。
作为 OA 的触发因素，机械应力可能会在小鼠和人类关节软骨中诱导 NF-κB 信号和 HIF-2α 的表达，这导致与软骨内骨化相关的分子的反式激活，其中最有效的 β-亚基伴侣是芳香烃核转位蛋白样（ARNTL）。与 HIF-2α 不同，HIF-1α 通过一种独特的机制来维持软骨，因此 HIF 的转移可能与 OA 的发病机制有关。
来自 NF-κB 信号到软骨内骨化相关分子的 HIF-2α 轴上的信号，可能与 HIF-2α 和 ARNTL 结合，可能代表 OA 的合理治疗靶点，对生理骨骼稳态的影响最小。
