Regulated in Development and DNA Damage Response 1 Deficiency Impairs Autophagy and Mitochondrial Biogenesis in Articular Cartilage and Increases the Severity of Experimental Osteoarthritis.
Regulated in Development and DNA Damage Response 1 Deficiency Impairs Autophagy and Mitochondrial Biogenesis in Articular Cartilage and Increases the Severity of Experimental Osteoarthritis.
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DOI：
10.1002/art.40104
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发表时间：
2017-07
期刊：
影响因子：
--
通讯作者：
Lotz MK
中科院分区：
文献类型：
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作者：
Alvarez-Garcia O;Matsuzaki T;Olmer M;Plate L;Kelly JW;Lotz MK
Redd1是一种内源性mTOR抑制物，调节细胞应激反应。Redd1在老年和骨关节炎(OA)软骨中的表达降低，并在体外调节关节软骨细胞的mTOR信号转导和自噬。本研究利用实验性骨性关节炎的小鼠模型，在体内研究了Redd1缺失的影响。对4个月大的野生型和接受内侧半月板手术失稳的Redd1−/−小鼠进行了骨关节炎严重程度的组织学评估。对Redd1+/+和Redd1+/+和Redd1−/−小鼠软骨细胞的自噬、细胞凋亡率、线粒体含量和线粒体生物发生标志物的表达进行了检测。在DMM模型中，Redd1缺乏增加了软骨、半月板软骨下骨和滑膜的变化。在氧化应激条件下，Redd1−/−小鼠的软骨细胞和培养的Redd1−/−软骨细胞的软骨细胞死亡增加。自噬关键标志(Lc3和ATG5)在Redd1−/−小鼠的软骨以及培养的人和小鼠软骨细胞中的表达显著减少。在Redd1基因缺陷的软骨细胞中，线粒体含量、三磷酸腺苷水平以及线粒体生物发生标志物Pgc1α和TFAM的表达也降低。在AMPK诱导的软骨细胞Pgc1α转录激活中，Redd1是必需的。我们的观察表明，Redd1是通过自噬和线粒体生物发生调节软骨内稳态的关键介质，并且Redd1缺乏加重了损伤诱导的OA的严重程度。
REDD1 is an endogenous inhibitor of mTOR that regulates cellular stress responses. REDD1 expression is decreased in aged and osteoarthritis (OA) cartilage and it regulates mTOR signaling and autophagy in articular chondrocytes in vitro. The present study investigated the effects of REDD1 deletion in vivo using a mouse model of experimental OA. Severity of OA was histologically assessed in 4-month-old wild-type and in Redd1−/− mice subjected to surgical destabilization of the medial meniscus (DMM). Chondrocyte autophagy, apoptosis, mitochondrial content, and expression of mitochondrial biogenesis makers were determined in cartilage and cultured chondrocytes from Redd1+/+ and Redd1−/− mice. REDD1 deficiency increased severity of changes in cartilage, menisci subchondral bone and synovium in the DMM model of OA. Chondrocyte death was increased in the cartilage of Redd1−/− mice and in cultured Redd1−/− chondrocytes under oxidative stress conditions. Expression of key autophagy markers (LC3 and ATG5) was markedly reduced in cartilage from Redd1−/− mice and in cultured human and mouse chondrocytes with REDD1 depletion. Mitochondrial content, ATP levels, and expression of the mitochondrial biogenesis markers PGC1α and TFAM were also decreased in REDD1 deficient chondrocytes. REDD1 was required for AMPK-induced PGC1α transcriptional activation in chondrocytes. Our observations suggest that REDD1 is a key mediator of cartilage homeostasis through regulation of autophagy and mitochondrial biogenesis and that REDD1 deficiency exacerbates the severity of injury-induced OA.