骨关节炎软骨细胞中线粒体生物发生受损，但可通过过氧化物酶体增殖物激活受体 γ 共激活因子 1α 逆转。
Mitochondrial biogenesis is impaired in osteoarthritis chondrocytes but reversible via peroxisome proliferator-activated receptor γ coactivator 1α.
机构信息
University of California at San Diego, La Jolla.
VA San Diego Healthcare System, San Diego, California.
出版信息
Arthritis Rheumatol. 2015 May;67(8):2141-53. doi: 10.1002/art.39182.
OBJECTIVE
The etiology of chondrocyte mitochondrial dysfunction in osteoarthritis (OA) is not completely understood. OA chondrocytes are deficient in the metabolic biosensors active AMP-activated protein kinase (AMPK) and sirtuin 1 (SIRT-1), which modulate the mitochondrial biogenesis "master regulator" peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α). Moreover, PGC-1α critically mediates AMPK anticatabolic activity in chondrocytes. The aim of this study was to test the hypothesis that mitochondrial biogenesis is deficient in human OA chondrocytes and that this deficiency functionally increases chondrocyte procatabolic responses, which are reversed by activation of the AMPK/SIRT-1/PGC-1α pathway.
METHODS
We assessed the expression and activity (phosphorylation) of AMPKα, SIRT-1, and PGC-1α in human knee chondrocytes and human and mouse knee cartilage, and we defined and compared the content and function of mitochondria, including oxidative phosphorylation and expression of mitochondrial biogenesis factors (mitochondrial transcriptional factor A [TFAM] and nuclear respiratory factors [NRFs]).
RESULTS
Human knee OA chondrocytes had a decreased mitochondrial biogenesis capacity, which was linked to reduced AMPKα activity and decreased expression of SIRT-1, PGC-1α, TFAM, NRF-1, and NRF-2. Human knee OA and aging mouse knee cartilage had decreased expression of TFAM and ubiquinol-cytochrome c reductase core protein, a subunit of mitochondrial complex III, in situ. Chondrocyte TFAM knockdown inhibited mitochondrial biogenesis and enhanced procatabolic responses to interleukin-1β. Finally, activation of AMPK by A-769662 increased PGC-1α expression via SIRT-1 and reversed impairments in mitochondrial biogenesis, oxidative phosphorylation, and intracellular ATP in human knee OA chondrocytes.
CONCLUSION
Mitochondrial biogenesis is deficient in human OA chondrocytes, and this deficiency promotes chondrocyte procatabolic responses. TFAM-mediated activation of the AMPK/SIRT-1/PGC-1α pathway reverses these effects, suggesting translational potential of pharmacologic AMPK activators to limit OA progression.
目的
骨关节炎（OA）中软骨细胞线粒体功能障碍的病因尚不完全清楚。OA 软骨细胞中代谢生物传感器活性 AMP 激活的蛋白激酶（AMPK）和沉默调节蛋白 1（SIRT-1）的含量减少，而这些物质可以调节线粒体生物发生的“主调控因子”过氧化物酶体增殖物激活受体 γ 共激活因子 1α（PGC-1α）。此外，PGC-1α 还可以介导 AMPK 在软骨细胞中的抗分解代谢活性。本研究旨在验证以下假设：即人 OA 软骨细胞中线粒体生物发生减少，这种缺陷会使软骨细胞的促分解代谢反应增加，并通过激活 AMPK/SIRT-1/PGC-1α 通路来逆转这种情况。
方法
我们评估了人膝关节软骨细胞以及人膝关节软骨和鼠膝关节软骨中 AMPKα、SIRT-1 和 PGC-1α 的表达和活性（磷酸化），并定义和比较了线粒体的含量和功能，包括氧化磷酸化和线粒体生物发生因子（线粒体转录因子 A [TFAM]和核呼吸因子 [NRFs]）的表达。
结果
人膝关节 OA 软骨细胞的线粒体生物发生能力降低，这与 AMPKα 活性降低以及 SIRT-1、PGC-1α、TFAM、NRF-1 和 NRF-2 的表达减少有关。人膝关节 OA 和衰老的鼠膝关节软骨中存在 TFAM 和 ubiquinol-cytochrome c reductase core protein（线粒体复合物 III 的一个亚单位）的原位表达减少。软骨细胞 TFAM 敲低抑制了线粒体生物发生，并增强了白细胞介素-1β诱导的促分解代谢反应。最后，通过 A-769662 激活 AMPK 通过 SIRT-1 增加 PGC-1α 的表达，并逆转了人膝关节 OA 软骨细胞中线粒体生物发生、氧化磷酸化和细胞内 ATP 的损伤。
结论
人 OA 软骨细胞中线粒体生物发生减少，这种缺陷促进了软骨细胞的促分解代谢反应。TFAM 介导的 AMPK/SIRT-1/PGC-1α 通路的激活逆转了这些影响，提示药理学 AMPK 激活剂具有限制 OA 进展的转化潜力。
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