Microfibrillar-associated protein 4 in health and disease

• Published in: Matrix biology Vol. 111; pp. 1 - 25
• Main Authors: Kanaan, Reine, Medlej-Hashim, Myrna, Jounblat, Rania, Pilecki, Bartosz, Sorensen, Grith L.
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 01.08.2022; Elsevier Science Ltd
• Subjects: Aging; Arteries; Asthma; Biomarkers; Chronic obstructive pulmonary disease; Collagen; Disease; Elastic fibers; Emphysema; Extracellular matrix; Fibrinogen; Fibrosis; Hepatitis C; Integrin signaling; Integrins; Liver diseases; Localization; Lung diseases; Matrix protein; Microfibrillar-associated protein 4; Obstructive lung disease; Phenotypes; Proteins; Remodeling; Tropoelastin; Elastic fibers; Microfibrillar-associated protein 4; Remodeling; Integrin signaling; Fibrosis; elastic fibers; remodeling; fibrosis; integrin signaling; microfibrillar-associated protein 4
• ISSN: 0945-053X; 1569-1802
• DOI: 10.1016/j.matbio.2022.05.008

•MFAP4 is a matrix protein promoting development and stability of elastic fibers.•MFAP4 is located predominantly at the elastin-microfibril interface in elastic tissues such as lung, blood vessels and skin.•During pathology, MFAP4 interaction with integrins leads to cell activation, inflammation and fibrosis.•MFAP4 shows potential as a diagnostic biomarker for liver fibrosis severity, while its usefulness in other diseases remains to be established.•We summarize and discuss the tissue distribution of MFAP4 and its reported role in health as well as various disease processes. 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 αVβ3 and αVβ5 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.