Kennedy Institute of Rheumatology, Nuffield Department of Orthopaedics Rheumatology and Musculoskeletal Science, University of Oxford, UK.
FEBS J. 2022 Jul;289(13):3603-3629. doi: 10.1111/febs.16039. Epub 2021 Jun 14.
Fibrosis of visceral organs such as the lungs, heart, kidneys and liver remains a major cause of morbidity and mortality and is also associated with many other disorders, including cancer and metabolic disease. In this review, we focus upon the microfibrillar collagen VI, which is present in the extracellular matrix (ECM) of most tissues. However, expression is elevated in numerous fibrotic conditions, such as idiopathic pulmonary disease (IPF), and chronic liver and kidney diseases. Collagen VI is composed of three subunits α1, α2 and α3, which can be replaced with alternate chains of α4, α5 or α6. The C-terminal globular domain (C5) of collagen VI α3 can be proteolytically cleaved to form a biologically active fragment termed endotrophin, which has been shown to actively drive fibrosis, inflammation and insulin resistance. Tissue biopsies have long been considered the gold standard for diagnosis and monitoring of progression of fibrotic disease. The identification of neoantigens from enzymatically processed collagen chains have revolutionised the biomarker field, allowing rapid diagnosis and evaluation of prognosis of numerous fibrotic conditions, as well as providing valuable clinical trial endpoint determinants. Collagen VI chain fragments such as endotrophin (PRO-C6), C6M and C6Mα3 are emerging as important biomarkers for fibrotic conditions.
内脏器官（如肺、心、肾和肝）的纤维化仍然是发病率和死亡率的主要原因，并且还与许多其他疾病有关，包括癌症和代谢疾病。在这篇综述中，我们重点关注存在于大多数组织细胞外基质（ECM）中的微纤维胶原 VI。然而，在许多纤维化疾病中，如特发性肺纤维化（IPF）和慢性肝、肾病，其表达水平升高。胶原 VI 由三个亚基 α1、α2 和 α3 组成，它们可以被交替的 α4、α5 或 α6 链取代。胶原 VI α3 的 C 末端球形结构域（C5）可以被蛋白水解切割形成具有生物活性的片段，称为内毒素素，它被证明可以积极地驱动纤维化、炎症和胰岛素抵抗。组织活检一直被认为是诊断和监测纤维化疾病进展的金标准。从酶处理的胶原链中鉴定出新抗原，彻底改变了生物标志物领域，使得许多纤维化疾病能够快速诊断和评估预后，并为临床试验终点的确定提供了有价值的信息。胶原 VI 链片段，如内毒素素（PRO-C6）、C6M 和 C6Mα3，正在成为纤维化疾病的重要生物标志物。
