Diverse functions of matrix metalloproteinases during fibrosis

Abstract

Fibrosis--a debilitating condition that can occur in most organs - is characterized by excess deposition of a collagen-rich extracellular matrix (ECM). At first sight, the activities of proteinases that can degrade matrix, such as matrix metalloproteinases (MMPs), might be expected to be under-expressed in fibrosis or, if present, could function to resolve the excess matrix. However, as we review here, some MMPs are indeed anti-fibrotic, whereas others can have pro-fibrotic functions. MMPs modulate a range of biological processes, especially processes related to immunity and tissue repair and/or remodeling. Although we do not yet know precisely how MMPs function during fibrosis--that is, the protein substrate or substrates that an individual MMP acts on to effect a specific process--experiments in mouse models demonstrate that MMP-dependent functions during fibrosis are not limited to effects on ECM turnover. Rather, data from diverse models indicate that these proteinases influence cellular activities as varied as proliferation and survival, gene expression, and multiple aspects of inflammation that, in turn, impact outcomes related to fibrosis.

Keywords: Collagen; Extracellular matrix; Fibrosis; Metalloproteinase; TIMP.

Fig. 1.

Model of the roles of MMPs and TIMPs in fibrosis. In this schematic, the pathogenesis of mammalian fibrosis is broken down into four sequential events, operating over a timescale of weeks to months in animal models and longer in human conditions. First, injury or some sort of damage initiates tissue remodeling responses. Second, an influx of inflammatory cells and the expression of cytokines by both resident and immune cells contribute to the third stage – activation of myofibroblasts and excessive deposition of extracellular collagen, giving the typical appearance of fibrosis. Finally, during the resolution phase, myofibroblasts undergo apoptosis or deactivation, and excess collagen and other matrix components are degraded and cleared. The clearance process can be delayed or inhibited, leading to chronic fibrotic disease, tissue malfunction, organ stress and, ultimately, end-stage disease. By either promoting (arrows) or antagonizing (T-shapes) these processes, specific MMPs and TIMPs have net pro-fibrotic (upper section) or anti-fibrotic (lower section) properties. (See Table 1 or text for references.)