Kalvaityte Ursule, Matta Csaba, Bernotiene Eiva, Pushparaj Peter Natesan, Kiapour Ata M, Mobasheri Ali
Department of Regenerative Medicine, State Research Institute Centre for Innovative Medicine, LT, 08406, Vilnius, Lithuania.
Department of Anatomy, Histology and Embryology, Faculty of Medicine, University of Debrecen, Debrecen, H, 4032, Hungary.
J Orthop Translat. 2021 Dec 10;32:77-84. doi: 10.1016/j.jot.2021.10.001. eCollection 2022 Jan.
Clusterin (CLU; also known as apolipoprotein J) is an ATP-independent holdase chaperone that prevents proteotoxicity as a consequence of protein aggregation. It is a ∼60 kDa disulfide-linked heterodimeric protein involved in the clearance of cellular debris and the regulation of apoptosis. CLU has been proposed to protect cells from cytolysis by complement components and has been implicated in Alzheimer's disease due to its ability to bind amyloid-β peptides and prevent aggregate formation in the brain. Recent studies suggest that CLU performs moonlighting functions. CLU exists in two major forms: an intracellular form and a secreted extracellular form. The intracellular form of CLU may suppress stress-induced apoptosis by forming complexes with misfolded proteins and facilitates their degradation. The secreted form of CLU functions as an extracellular chaperone that prevents protein aggregation.
In this review, we discuss the published literature on the biology of CLU in cartilage, chondrocytes, and other synovial joint tissues. We also review clinical studies that have examined the potential for using this protein as a biomarker in synovial and systemic fluids of patients with rheumatoid arthritis (RA) or osteoarthritis (OA).
Since CLU functions as an extracellular chaperone, we propose that it may be involved in cytoprotective functions in osteoarticular tissues. The secreted form of CLU can be measured in synovial and systemic fluids and may have translational potential as a biomarker of early repair responses in OA.
There is significant potential for investigating synovial and systemic CLU as biomarkers of OA. Future translational and clinical orthopaedic studies should carefully consider the diverse roles of this protein and its involvement in other comorbidities. Therefore, future biomarker studies should not correlate circulating CLU levels exclusively to the process of OA pathogenesis and progression. Special attention should be paid to CLU levels in synovial fluid.
There is significant potential for investigating synovial and systemic CLU as a predictive biomarker of osteoarthritis (OA) progression and response to novel treatments and interventions. Given that CLU plays diverse roles in other comorbidities such as rheumatoid arthritis (RA) and obesity, future translational and clinical orthopaedic biomarker studies should not directly correlate circulating CLU levels to the process of OA pathogenesis and progression. However, special attention should be paid to CLU levels in synovial fluid. The cytoprotective properties of CLU may support the implementation of regenerative strategies and new approaches for developing targeted therapeutics for OA.
簇集素（CLU；也称为载脂蛋白J）是一种不依赖ATP的分子伴侣，可防止蛋白质聚集导致的蛋白毒性。它是一种约60 kDa的二硫键连接的异源二聚体蛋白，参与细胞碎片清除和细胞凋亡调控。有人提出CLU可保护细胞免受补体成分的细胞溶解作用，并且由于其能够结合淀粉样β肽并防止大脑中聚集体形成，因而与阿尔茨海默病有关。最近的研究表明CLU具有兼职功能。CLU以两种主要形式存在：细胞内形式和分泌到细胞外的形式。细胞内形式的CLU可能通过与错误折叠的蛋白质形成复合物来抑制应激诱导的细胞凋亡，并促进其降解。分泌形式的CLU作为细胞外分子伴侣发挥作用，可防止蛋白质聚集。
在本综述中，我们讨论了已发表的关于CLU在软骨、软骨细胞和其他滑膜关节组织中的生物学研究文献。我们还回顾了一些临床研究，这些研究探讨了将该蛋白用作类风湿性关节炎（RA）或骨关节炎（OA）患者滑膜液和全身液体中生物标志物的潜力。
由于CLU作为细胞外分子伴侣发挥作用，我们提出它可能参与骨关节组织的细胞保护功能。可以在滑膜液和全身液体中检测到分泌形式的CLU，并且它可能具有作为OA早期修复反应生物标志物的转化潜力。
将滑膜和全身的CLU作为OA生物标志物进行研究具有很大潜力。未来的转化和临床骨科研究应仔细考虑该蛋白的多种作用及其在其他合并症中的参与情况。因此，未来的生物标志物研究不应仅将循环中的CLU水平与OA发病机制和进展过程相关联。应特别关注滑膜液中的CLU水平。
将滑膜和全身的CLU作为骨关节炎（OA）进展以及对新治疗和干预措施反应的预测性生物标志物进行研究具有很大潜力。鉴于CLU在类风湿性关节炎（RA）和肥胖症等其他合并症中发挥多种作用，未来的转化和临床骨科生物标志物研究不应直接将循环中的CLU水平与OA发病机制和进展过程相关联。然而，应特别关注滑膜液中的CLU水平。CLU的细胞保护特性可能支持再生策略的实施以及开发针对OA的靶向治疗新方法。
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