Regulation of autophagy in human and murine cartilage: hypoxia-inducible factor 2 suppresses chondrocyte autophagy.
Regulation of autophagy in human and murine cartilage: hypoxia-inducible factor 2 suppresses chondrocyte autophagy.
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DOI：
10.1002/art.24444
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发表时间：
2009-05
影响因子：
--
通讯作者：
Srinivas, Vickram
中科院分区：
文献类型：
--
作者：
Bohensky, Jolene;Terkhorn, Shawn P.;Freeman, Theresa A.;Adams, Christopher S.;Garcia, Joseph A.;Shapiro, Irving M.;Srinivas, Vickram
我们之前已经证明转录因子 HIF-1 促进软骨细胞自噬的发生。本研究的总体目标是检验另一个 HIF 家族转录因子 HIF-2 调节软骨细胞自噬诱导的假设。通过免疫组织化学观察 HIF-1、HIF-2 和 LC-3 的表达。使用 siRNA 技术实现了 HIF-2 的抑制。对细胞培养物中的软骨细胞的自噬流、溶酶体活性和超微结构分析进行了评估。 HIF-2 在小鼠和人类关节软骨以及矿化椎骨软骨中的细胞中大量表达。年长动物的关节软骨、终板软骨和人骨关节炎软骨细胞中的蛋白质水平降低。 HIF-2 在小鼠生长软骨的肥大前细胞中强烈表达。当 HIF-2α 被沉默时，ROS 生成增加，同时过氧化氢酶和超氧化物歧化酶活性降低。 HIF-2 的抑制与 Akt-1 和 mTOR 活性降低、Bcl-XL 表达降低以及强自噬反应相关，即使在营养充足的条件下也是如此；在这些沉默的软骨细胞中，HIF-1 表达升高。 HIF-2 表达减少与骨关节炎组织和老化软骨中的自噬相关。最后，我们检测了 HIF-2α 敲除小鼠生长板中软骨细胞的自噬反应。整个板的自噬反应升高。基于上述观察，得出结论：HIF-2是成熟软骨细胞自噬的有效调节剂。我们的数据表明，这种蛋白质充当 HIF-1 自噬加速器功能的制动器。
We have previously demonstrated that the transcription factor, HIF-1, promoted the onset of autophagy in chondrocytes. The overall goal of this study was to test the hypothesis that another HIF family transcription factor, HIF-2, modulated the induction of autophagy by chondrocytes. Expression of HIF-1, HIF-2 and LC-3 were visualized by immunohistochemistry. Suppression of HIF-2 was achieved using siRNA technology. Autophagic flux, lysosomal activity and ultrastructural analysis was assessed in chondrocytes in cell culture. HIF-2 was expressed abundantly by cells in mouse and human articular cartilage and the cartilage of mineralizing vertebrae. Protein levels were reduced in articular cartilage of older animals, the end plate cartilage and in human osteoarthritic chondrocytes. HIF-2 was robustly expressed in the pre-hypertrophic cells of the mouse growth cartilage. When HIF-2α was silenced, ROS generation was elevated with a concomitant decrease in catalase and superoxide dismutase activity. Suppression of HIF-2 was associated with decreased Akt-1 and mTOR activities, reduced Bcl-XL expression and a robust autophagic response even under nutrient replete conditions; in these silenced chondrocytes, HIF-1 expression was elevated. Decreased HIF-2 expression was associated with autophagy in osteoarthritic tissue and aging cartilages. Finally, we examined the autophagic response of chondrocytes in HIF-2α knockout mouse growth plate. There was elevated autophagic response throughout the plate. Based on the above mentioned observations, it is concluded that HIF-2 is a potent regulator of autophagy in maturing chondrocytes. Our data suggests that this protein acts as a brake to the autophagy accelerator function of HIF-1.
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影响因子：
5.3
作者：
Park, SK;Dadak, AM;Johnson, RS
通讯作者：
Johnson, RS
影响因子：
13.3
作者：
Bohensky, Jolene;Shapiro, Irving M.;Srinivas, Vickram
通讯作者：
Srinivas, Vickram
影响因子：
13.3
作者：
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影响因子：
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作者：
Watanabe, Hitoshi;Bohensky, Jolene;Freeman, Theresa;Srinivas, Vickram;Shapiro, Irving M.
通讯作者：
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影响因子：
5.6
作者：
Bohensky, Jolene;Shapiro, Irving M.;Srinivas, Vickram
通讯作者：
Srinivas, Vickram