Extracellular vesicle-associated MMPs: A modulator of the tissue microenvironment

Abstract

Extracellular vesicles (EVs) are small particles that mediate intercellular communications in local and distant microenvironments. Due to their ability to carry bioactive materials such as proteins, nucleic acids, and lipids, and to transfer their cargo into target cells, EVs are thought to be crucial mediators under pathological and physiological conditions. Recent investigations of their protein profiles have revealed the presence of metalloproteinases such as matrix metalloproteinases (MMPs) in EVs from various cell types and body fluids. Although information regarding the biological and clinical significance of MMPs in EVs is still limited, EV-associated MMPs can alter EV cargo by ectodomain shedding, exerting proteolytic activity following uptake by target cells, or directly contributing to degradation of extracellular matrix proteins surrounding cells. This review focuses on recent findings regarding EV-associated MMPs, and we further discuss their potential involvement in human diseases.

Introduction

Cell-cell communication plays crucial roles in developmental, physiological, and pathological processes. Cells are thought to communicate with their neighbors or with distant cells through ligand-receptor interaction, the secretion of soluble factors, such as cytokines, chemokines, and growth factors, or through the transfer of cytoplasmic components through junctional coupling. However, another mode of intercellular communication via extracellular vesicles (EVs) has become a subject of increasing interest [1]. EVs are small membrane vesicles containing various bioactive materials such as proteins, lipids, RNA, and DNA, which are transferred to target cells. EVs have been shown to influence neighboring and distant target cells by inducing intracellular signaling through receptor binding or by transferring new properties such as receptors, enzymes, or even genetic material from the vesicles. EVs have also been implicated in the pathogenesis of multiple diseases [2].

Metalloproteinases, which are characterized by a requirement for a divalent metal ion for proteolytic activity, are the largest class of catalytic enzymes [3]. These enzymes can be subdivided into 27 families, and within these families, the metzincin superfamily consists of 23 matrix metalloproteinases (MMPs), 25 ADAMs (short for “a disintegrin and metalloproteinase”), and 19 ADAMs with thrombospondin motifs (ADAMTSs) [4], [5], [6]. They can extensively degrade extracellular matrix (ECM) proteins or selectively release cell surface-bound cytokines, growth factors, or their receptors, thereby impacting ECM integrity, immune cell recruitment, and tissue turnover. Recent proteomic analyses have revealed that EVs from various cell types and bodily fluids contain metalloproteinases such as MMPs [7], [8], [9], [10]. Importantly, several metalloproteinases in EVs have been shown to exhibit proteolytic properties and participate in pathological processes. For example, EVs in cancer tissues harbor MMP-2 and MMP-9, which are involved in local invasion, and ADAMTSs have been detected in EVs from synovial fluids and may contribute to the degradation and remodeling of the aggrecan-rich ECM in arthritis. Thus, although information regarding MMPs in EVs is limited, EV-associated MMPs can alter EV cargo by ectodomain shedding, exerting proteolytic activity following uptake by target cells, or directly contributing to the degradation of ECM proteins surrounding cells. In this review, we outline the current knowledge on EV-associated metalloproteinases, especially MMPs, and further discuss their potential roles and clinical significance under pathological conditions.