线粒体质量控制在骨关节炎中的研究进展

doi:10.3877/cma.j.issn.1674-134X.2024.02.009

骨关节炎(OA)是一种多因素导致的退行性骨骼肌肉疾病关节疾病，发病率和致残率较高，严重影响患者的生活质量，临床上现有的非手术治疗手段对OA的延缓和逆转效果有限，晚期的OA患者均不可避免地要接受全关节置换。线粒体是细胞的能量代谢中心，参与细胞内的多种生物反应过程并发挥着重要作用，线粒体质量控制(MQC)是一种细胞内源性保护程序，能够通过多维度调节线粒体的形态、数量、质量和功能来限制线粒体损伤，对于维持线粒体网格的稳态以及线粒体功能的正常发挥有重要意义。越来越多的研究表明，MQC与包括OA在内的多种年龄退行性疾病密切相关，并可能成为这些疾病潜在的治疗靶点。本文总结概述了OA软骨细胞中与线粒体功能障碍相关的异常MQC调控策略，并讨论了目前与MQC相关的具有临床转化潜力的分子策略，以期能够为OA的诊断和治疗提供新思路。

关键词: 骨关节炎, 线粒体, 治疗

Osteoarthritis (OA) is a multifactorial degenerative musculoskeletal disease joint disease with high morbidity and disability, which seriously affects the quality of life of patients. Clinically available non-surgical treatments have limited effects on the delay and reversal of OA, and patients with advanced OA inevitably have to undergo total joint replacement. Mitochondria are the energy metabolism center of the cell, participating in a variety of intracellular biological reaction processes and playing an important role. Mitochondrial quality control (MQC) is a kind of cellular endogenous protection program, which is able to regulate the morphology, quantity, quality, and function of the mitochondria in a multidimensional manner to limit mitochondrial damage, and it is important for the maintenance of mitochondrial lattice homeostasis as well as the normal play of the mitochondrial function. A growing number of studies have shown that MQC is closely associated with a variety of age-degenerative diseases, including OA, and may be a potential therapeutic target for these diseases. This paper summarized and outlined the aberrant MQC regulatory strategies associated with mitochondrial dysfunction in OA chondrocytes and discussed the current molecular strategies associated with MQC that have clinical translational potential, with the aim of providing new ideas for the diagnosis and treatment of OA.

Key words: Osteoarthritis, Mitochondrion, Therapy

图1 OA(骨关节炎)患者的MQC(线粒体质量控制)的三个主要过程及参与OA进展的关键分子

Figure 1 Three main processes of MQC of OA patients and key molecules involved in OA process

表1 OA中线粒体生物发生的关键调控分子

Table 1 Key regulatory molecules of mitochondrial biogenesis in OA

调节因子	表达水平	功能	参考文献
TFAM	下调	抑制线粒体生物合成，并促进对IL-1β的分解代谢反应	Wang ^[34]
PGC1-α	下调	通过限制氧化应激，抑制促分解代谢反应来抑制OA的进展	Ji ^[44]
SIRT1	下调	增加COL X、MMP-13、ADAMTS-5凋亡和标志物的表达水平的表达，进而促进OA的进展	Matsuzaki ^[48]
SIRT3	下调	使细胞内具有抗氧化功能的蛋白处于乙酰化状态，从而引起氧化应激，破坏软骨细胞稳态并促进软骨细胞的凋亡，最终导致OA的进展	Zhao ^[46] Chen ^[54]

表1 OA中线粒体生物发生的关键调控分子

Table 1 Key regulatory molecules of mitochondrial biogenesis in OA

调节因子	表达水平	功能	参考文献
TFAM	下调	抑制线粒体生物合成，并促进对IL-1β的分解代谢反应	Wang ^[34]
PGC1-α	下调	通过限制氧化应激，抑制促分解代谢反应来抑制OA的进展	Ji ^[44]
SIRT1	下调	增加COL X、MMP-13、ADAMTS-5凋亡和标志物的表达水平的表达，进而促进OA的进展	Matsuzaki ^[48]
SIRT3	下调	使细胞内具有抗氧化功能的蛋白处于乙酰化状态，从而引起氧化应激，破坏软骨细胞稳态并促进软骨细胞的凋亡，最终导致OA的进展	Zhao ^[46] Chen ^[54]

表2 OA中线粒体动力学的关键调控分子

Table 2 Key regulatory molecules of mitochondrial dynamics in OA

调节因子	表达水平	功能	参考文献
DRP1	上调	增强炎性软骨细胞内的线粒体分裂	Shin ^[69] Wang ^[72]
MFN1	上调	增强炎性软骨细胞内的线粒体分裂	Shin ^[69] Wang ^[72]
MFN2	上调	促进代谢变化以及炎症及OA的进展，同时能够抑制Parkin的表达	Xu ^[77]

表2 OA中线粒体动力学的关键调控分子

Table 2 Key regulatory molecules of mitochondrial dynamics in OA

调节因子	表达水平	功能	参考文献
DRP1	上调	增强炎性软骨细胞内的线粒体分裂	Shin ^[69] Wang ^[72]
MFN1	上调	增强炎性软骨细胞内的线粒体分裂	Shin ^[69] Wang ^[72]
MFN2	上调	促进代谢变化以及炎症及OA的进展，同时能够抑制Parkin的表达	Xu ^[77]

表3 OA中与线粒体自噬有关的潜在调控通路

Table 3 Potential regulatory pathways related to mitochondrial autophagy in OA

信号通路	表达水平	作用	参考文献
Parkin介导的信号通路	增强	降低ROS的水平，提高软骨细胞的存活率	Shin ^[69]
PINK1介导的信号通路	增强	加剧软骨损伤	Shin ^[69]
SIRT3-FoxO3a-Parkin	抑制	减轻软骨损伤	He ^[51] Petursson ^[52]
SIRT3-PINK1-Parkin	抑制	保护软骨细胞	Wang ^[73]

表3 OA中与线粒体自噬有关的潜在调控通路

Table 3 Potential regulatory pathways related to mitochondrial autophagy in OA

信号通路	表达水平	作用	参考文献
Parkin介导的信号通路	增强	降低ROS的水平，提高软骨细胞的存活率	Shin ^[69]
PINK1介导的信号通路	增强	加剧软骨损伤	Shin ^[69]
SIRT3-FoxO3a-Parkin	抑制	减轻软骨损伤	He ^[51] Petursson ^[52]
SIRT3-PINK1-Parkin	抑制	保护软骨细胞	Wang ^[73]

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Advances in strategies for regulating extracellular vesicle formation and biological function

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Advances in strategies for regulating extracellular vesicle formation and biological function