Cell Dynamics Research Center and School of Life Sciences, Gwangju Institute of Science and Technology, Gwangju, Korea.
Cell Death Differ. 2012 Mar;19(3):440-50. doi: 10.1038/cdd.2011.111. Epub 2011 Aug 26.
Apoptosis of articular chondrocytes is associated with the pathogenesis of osteoarthritis (OA). Recently, we demonstrated that hypoxia-inducible factor (HIF)-2α, encoded by Epas1, causes OA cartilage destruction by regulating the expression of various matrix-degrading enzymes. Here, we investigated the involvement of HIF-2α in chondrocyte apoptosis and OA cartilage destruction. HIF-2α levels in human and mouse OA chondrocytes were markedly elevated in association with increased apoptosis of articular chondrocytes. Overexpression or knockdown of HIF-2α alone did not cause chondrocyte apoptosis. However, HIF-2α expression markedly increased chondrocyte apoptosis in the presence of an agonistic anti-Fas (CD95) antibody. HIF-2α enhanced Fas expression and potentiated downstream signaling pathways, increasing the activity of initiator and executioner caspases. Overexpression of HIF-2α in mouse cartilage tissue, either by intra-articular injection of Epas1 adenovirus (Ad-Epas1) or in the context of chondrocyte-specific Epas1 transgenic mice, increased chondrocyte apoptosis and cartilage destruction. In contrast, chondrocyte-specific knockout of Epas1 in mice suppressed DMM (destabilization of the medial meniscus)-induced chondrocyte apoptosis and inhibited OA cartilage destruction. Moreover, Fas-deficient mice exhibited diminished chondrocyte apoptosis and OA cartilage destruction in response to Ad-Epas1 injection or DMM surgery. Taken together, our results demonstrate that HIF-2α potentiates Fas-mediated chondrocyte apoptosis, which is associated with OA cartilage destruction.
关节软骨细胞的凋亡与骨关节炎（OA）的发病机制有关。最近，我们证明，缺氧诱导因子（HIF）-2α通过调节各种基质降解酶的表达导致 OA 软骨破坏，其由 Epas1 编码。在这里，我们研究了 HIF-2α 在软骨细胞凋亡和 OA 软骨破坏中的作用。人 OA 软骨细胞和鼠 OA 软骨细胞中的 HIF-2α 水平明显升高，与关节软骨细胞凋亡增加有关。单独过表达或敲低 HIF-2α 本身不会引起软骨细胞凋亡。然而，在存在激动性抗 Fas（CD95）抗体的情况下，HIF-2α 表达明显增加了软骨细胞凋亡。HIF-2α 增强 Fas 表达并增强下游信号通路，增加起始和执行半胱氨酸蛋白酶的活性。通过关节内注射 Epas1 腺病毒（Ad-Epas1）或在软骨细胞特异性 Epas1 转基因小鼠的背景下，过表达 HIF-2α，可增加软骨细胞凋亡和软骨破坏。相反，在小鼠中特异性敲除 Epas1 可抑制 DMM（内侧半月板不稳定）诱导的软骨细胞凋亡并抑制 OA 软骨破坏。此外，Fas 缺陷型小鼠在接受 Ad-Epas1 注射或 DMM 手术后，软骨细胞凋亡和 OA 软骨破坏减少。总之，我们的结果表明，HIF-2α 增强 Fas 介导的软骨细胞凋亡，与 OA 软骨破坏有关。
