Kong Wenyu, Lyu Cheng, Liao Hongen, Du Yanan
Department of Biomedical Engineering, School of Medicine, Tsinghua-Peking Center for Life Sciences, Tsinghua University, Beijing 100084, People's Republic of China.
Department of Biomedical Engineering, School of Medicine, Tsinghua University, Beijing 100084, People's Republic of China.
Biomed Mater. 2021 Oct 19;16(6). doi: 10.1088/1748-605X/ac2b79.
Biophysical properties of extracellular matrix (ECM), such as matrix stiffness, viscoelasticity and matrix fibrous structure, are emerging as important factors that regulate progression of fibrosis and other chronic diseases. The biophysical properties of the ECM can be rapidly and profoundly regulated by crosslinking reactions in enzymatic or non-enzymatic manners, which further alter the cellular responses and drive disease progression. In-depth understandings of crosslinking reactions will be helpful to reveal the underlying mechanisms of fibrosis progression and put forward new therapeutic targets, whereas related reviews are still devoid. Here, we focus on the main crosslinking mechanisms that commonly exist in a plethora of chronic diseases (e.g. fibrosis, cancer, osteoarthritis) and summarize current understandings including the biochemical reaction, the effect on ECM properties, the influence on cellular behaviors, and related studies in disease model establishment. Potential pharmaceutical interventions targeting the crosslinking process and relevant clinical studies are also introduced. Limitations of pharmaceutical development may be due to the lack of systemic investigations related to the influence on crosslinking mechanism from micro to macro level, which are discussed in the last section. We also propose the unclarified questions regarding crosslinking mechanisms and potential challenges in crosslinking-targeted therapeutics development.
细胞外基质（ECM）的生物物理特性，如基质硬度、粘弹性和基质纤维结构，正逐渐成为调节纤维化和其他慢性疾病进展的重要因素。ECM的生物物理特性可通过酶促或非酶促交联反应迅速而深刻地调节，这进一步改变细胞反应并推动疾病进展。深入了解交联反应将有助于揭示纤维化进展的潜在机制并提出新的治疗靶点，然而相关综述仍然缺乏。在此，我们聚焦于多种慢性疾病（如纤维化、癌症、骨关节炎）中普遍存在的主要交联机制，并总结当前的认识，包括生化反应、对ECM特性的影响、对细胞行为的影响以及疾病模型建立中的相关研究。还介绍了针对交联过程的潜在药物干预措施及相关临床研究。药物开发的局限性可能归因于缺乏从微观到宏观层面关于交联机制影响的系统性研究，这将在最后一部分进行讨论。我们还提出了关于交联机制尚未阐明的问题以及交联靶向治疗开发中的潜在挑战。
