Mitochondrial dysfunction in osteoarthritis
Mitochondrial dysfunction in osteoarthritis
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DOI：
10.1016/j.mito.2004.07.022
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发表时间：
2004-09-01
期刊：
影响因子：
4.4
通讯作者：
Maneiro, E
中科院分区：
文献类型：
--
作者：
Blanco, FJ;López-Armada, MJ;Maneiro, E
在骨关节炎（OA）中，时间或年龄依赖性过程导致软骨结构异常，其特征是软骨细胞数量减少，现有软骨细胞外基质丢失，生成成分异常的基质和病理性基质钙化。由于软骨细胞基质的合成和矿化是由ATP生成和消耗之间的平衡调节的，因此软骨细胞产生能量的机制一直是一个感兴趣的话题。OA软骨细胞线粒体呼吸链（MRC）活性分析显示，与正常软骨细胞相比，复合物II和III显著降低。另一方面，线粒体质量在OA中增加，正如CS活性显著升高所证明的那样。此外，通过荧光探针JC-1发现，OA细胞显示线粒体膜电位（Deltapsim）降低。OA软骨中含有大量凋亡的软骨细胞，线粒体在凋亡中起关键作用。有趣的是，OA软骨显示Bcl-2和caspasa-3的表达明显升高。这种表达也与软骨细胞凋亡和OA病变相关。骨性关节炎的发病机制包括IL-1、tnf - α等因素诱导软骨细胞诱导的NO合成酶上调，导致NO数量增加。一氧化氮降低软骨细胞存活，诱导细胞死亡，并伴有软骨细胞凋亡的形态学改变。NO降低配合物IV的活性，降低Deltapsim（红/绿荧光比）。NO诱导caspase-3和-7 mRNA的表达，降低bcl-2 mRNA的表达和bcl-2蛋白的合成。一些研究表明，软骨细胞线粒体是钙转运的特化细胞，在细胞外基质的钙化中起重要作用。矿物形成已证实在基质囊泡（MV）和线粒体内。直接抑制线粒体呼吸促进了mv介导的软骨细胞矿化。MRC的调控可能是NO调控关节软骨基质生物合成和病理矿化的信号通路之一。40岁以后，OA在人类中的发病率随着年龄的增长而逐渐增加。研究表明，年龄与人正常软骨细胞复合体I活性降低之间有统计学意义的趋势。然而，年龄与正常软骨细胞Deltapsim之间的关系研究并未显示出任何显著相关性。据报道，随着种群数量的增加，线粒体DNA被降解，每个软骨细胞的线粒体数量下降。确定线粒体在OA中的作用的一种方法是确定MRC抑制的作用，并将其与OA中的发现进行比较。用抗霉素抑制MRC可阻止TGFbeta增加Pi排泄的正常能力，从而恶化病理性HA晶体的沉积。在软骨细胞中，抑制复合物IV与NaN3修饰A（pm）和诱导细胞凋亡的细胞存活。鱼藤酮抑制复合物I可增加Bcl-2和Cox-2的表达和合成，其作用与IL-1在人软骨细胞中产生的作用相似。(C) 2004 Elsevier B.V.与线粒体研究学会。所有航班预订。
In osteoarthritis (OA) a time or age dependent process leads to aberrant cartilage structure which is characterized by reduced number of chondrocytes, loss of existing cartilage extracellular matrix, the production of matrix with abnormal composition and pathologic matrix calcification. Because chondrocyte matrix synthesis and mineralization are modulated by the balance between ATP generation and consumption, the mechanism by which chondrocytes generate energy have been a topic of interest. The analysis of mitochondrial respiratory chain (MRC) activity in OA chondrocytes shows a significant decrease in complexes II and III compared to normal chondrocytes. On the other hand, mitochondrial mass is increased in OA, as demonstrated by a significant rise in CS activity. Furthermore, OA cells show a reduction in the mitochondrial membrane potential (Deltapsim) as demonstrated by using the fluorescent probe JC-1. OA cartilage contains high number of apoptotic chondrocytes, and mitochondria play a key role in apoptosis. Interestingly, OA cartilages show markedly elevated Bcl-2 and caspasa-3 expression. This expression is also correlated with chondrocyte apoptosis and OA lesions. The pathogenesis of OA includes elaboration of increased amounts of NO as a consequence of up-regulation of chondrocyte-inducible NO synthase induced by IL-1, TNF-alpha and other factors. NO reduces chondrocyte survival and induces cell death with morphologic changes characteristic of chondrocyte apoptosis. NO reduces the activity of complex IV and decreases the Deltapsim as measured as the ratio of red/green fluorescence. Furthermore, NO induces the mRNA expression of caspase-3 and -7, and it reduces the expression of mRNA bcl-2 and the bcl-2 protein synthesis.Some studies suggest that the chondrocyte mitochondria are specialized for calcium transport and are important in the calcification of the extracellular matrix. Mineral formation has been demonstrated in matrix vesicles (MV) and within mitochondria. Direct suppression of mitochondrial respiration promoted MV-mediated mineralization in chondrocytes. Regulation of MRC may be one of the signaling pathways by which NO modulates articular cartilage matrix biosynthesis and pathologic mineralization. After age 40, the incidence of OA in humans increases progressively with increasing age. Studies show a trend to statistic significance between the age and the reduction of complex I activity of human normal chondrocytes. However, the study of relation between age and Deltapsim in normal chondrocytes do not demonstrate any significant correlation. It has been reported that as the number of population doublings increased, mitochondrial DNA was degraded and the number of mitochondria per chondrocyte decline. One approach for determining the role of mitochondria in OA is to determine the effects of the MRC inhibition and to compare them with the findings in OA. Inhibition of MRC with antimycin prevents the normal ability of TGFbeta to increase excretion of Pi, thereby worsening deposition of pathologic HA crystals. In chondrocytes, the inhibition of complex IV with NaN3 modified both the A(pm and the survival of cells inducing apoptosis. Inhibition of complex I with rotenone increases the expression and synthesis of Bcl-2 and Cox-2, both effects are similar effects to produced by IL-1 in human chondrocytes. (C) 2004 Elsevier B.V. and Mitochondria Research Society. All fights reserved.