Microfibrillar-associated protein 4 (MFAP4) is an extracellular matrix protein belonging to the fibrinogen-related domain family. It has been localized to elastic fiber-rich regions in several tissues including the arteries, lungs, heart and skin. MFAP4 binds collagen, fibrillins and tropoelastin and contributes to the process of microfibrillar assembly and maturation of elastic fibers. MFAP4 can also bind RGD-dependent integrins, predominantly α_Vβ₃ and α_Vβ₅ through its N-terminal RGD sequence, modulating cellular behavior. Circulating MFAP4 was suggested as a robust biomarker for hepatitis C virus- and alcoholic liver disease-related liver fibrosis, cardiovascular disorders and chronic obstructive pulmonary disease. In mice, MFAP4 seems to have a widely redundant role under homeostatic conditions, as global MFAP4 deficiency results in a mild pulmonary phenotype, causing emphysema-like airspace enlargement that progresses with age. However, emerging in vivo and in vitro data suggest that MFAP4 is actively involved in the pathogenesis of remodeling-associated diseases, including fibrosis, cardiovascular disorders, aging, asthma and cancer through activation of integrin-mediated signaling as well as by modulating TGF-β pathway, thus supporting maladaptive matrix remodeling. This review summarizes the current knowledge about MFAP4 structure and localization, its mechanisms of action in disease-induced tissue remodeling as well as its potential role as a clinical biomarker.

微纤维相关蛋白 4 (MFAP4) 是一种细胞外基质蛋白，属于纤维蛋白原相关域家族。它已定位于包括动脉、肺、心脏和皮肤在内的几种组织中富含弹性纤维的区域。MFAP4 结合胶原蛋白、原纤维蛋白和原弹性蛋白，并有助于微纤维组装和弹性纤维成熟的过程。MFAP4 还可以结合 RGD 依赖性整联蛋白，主要是 α _V β ₃和 α _V β ₅通过其 N 端 RGD 序列，调节细胞行为。循环 MFAP4 被认为是丙型肝炎病毒和酒精性肝病相关肝纤维化、心血管疾病和慢性阻塞性肺病的有力生物标志物。在小鼠中，MFAP4 似乎在稳态条件下具有广泛的冗余作用，因为全球 MFAP4 缺乏导致轻度肺表型，导致随着年龄的增长而出现肺气肿样空域扩大。然而，在体内和体外出现数据表明，MFAP4 通过激活整合素介导的信号传导以及调节 TGF-β 通路，积极参与重塑相关疾病的发病机制，包括纤维化、心血管疾病、衰老、哮喘和癌症，从而支持适应不良的基质重塑。本综述总结了目前关于 MFAP4 结构和定位的知识、其在疾病诱导的组织重塑中的作用机制以及其作为临床生物标志物的潜在作用。