Mini reviewMatrix metalloproteinase-8: Cleavage can be decisive
Introduction
The matrix metalloproteinase (MMP) family consists of a group of 25 related Zn2+-dependent endoproteases. It was originally believed that the function of these MMPs is restricted to ECM turnover and degradation. However, later studies revealed that many non-structural substrates can also be cleaved by MMPs, thereby influencing both physiological and pathological processes. One of the most intriguing MMPs, MMP-8, also known as collagenase-2 or neutrophil collagenase, was long thought to be expressed solely in neutrophil precursors during late myeloid maturation. However, it has become evident that MMP-8 can be expressed in a wide range of cells (Table 1), mainly in the course of different inflammatory conditions. Many studies have reported that MMP-8 is indeed associated with a wide range of inflammatory disorders, as well as cancer progression. The recent generation of MMP-8 deficient mice has allowed researchers to directly test the role of MMP-8 in a wide range of pathological conditions, which has strengthened the idea that MMP-8 is a central mediator in both acute and chronic inflammation.
Because MMPs can have such a great impact, their activity is tightly regulated. Like most MMPs, MMP-8 is secreted as an inactive pro-enzyme that needs to be activated before it can exert its function. This pro-form of MMP-8 contains an N-terminal pro-domain, typical for all MMPs, with a cysteine residue that interacts with the Zn2+ ion at the active site to block all proteolytic activity. Only by disrupting this mechanism, either by proteolytically removing the pro-domain or by modifying the cysteine thiol group can the pro-enzyme be converted into an active protease, a process known as the cysteine-switch mechanism (Fig. 1) [1]. This conversion can be mediated by reactive oxygen species released from activated neutrophils [2], or by a variety of proteases. Both cathepsin G [3] and chymotrypsin [3] can activate MMP-8, as well as several MMPs such as MMP-3 [4], MMP-7 [5], MMP-10 [6], and MMP-14 [7], and even several bacterial proteases [8]. This indicates that MMP-8 activation is indeed strongly regulated and mostly limited to sites of inflammation.
Apart from the PMN-derived full-length MMP-8 (80 kDa) and its 75-kDa activated form devoid of the pro-domain, several other MMP-8 species with a much smaller molecular weight (40–60 kDa) have been identified. These forms are poorly glycosylated compared to PMN-derived MMP-8 [9], [10], [11], [12], [13]. Further experiments revealed that this high degree of glycosylation of PMN-derived MMP-8 is associated with the storage of the enzyme in the intracellular granules of those neutrophils. This explains why poorly glycosylated MMP-8, which is produced by other cell types, is not retained within the cell but is promptly secreted in the extracellular compartment after synthesis [14], [15]. It is also noteworthy that although MMP-8 does not contain a transmembrane-domain or a GPI anchor, as in membrane-associated MMPs, Owen et al. have described a PMN membrane-bound MMP-8 form [16]. Membrane-associated MMP-8 appears to be more stable and more resistant to TIMP inhibition than the soluble secreted form.
Once activated, MMP-8 can cleave a wide range of substrates (Table 2). Besides being an efficient collagen degrading protease (collagen type I > type III > type II), MMP-8 also cleaves a wide range of non-collagenous substrates, such as serine protease inhibitors and several chemokines. This allows MMP-8 to influence the biological activities of many of these substrates, since cleavage can either lead to their inactivation [17] or to an increase in their biological activities [18]. However, the concept of ECM breakdown and its effects is also evolving, because ECM cleavage involves more than just breaking down a barrier. It can lead to the release of many ECM-associated signalling factors, as well as cryptic ECM fragments possessing biological activities.
Section snippets
Collagenase-2 at different stages of cancer progression
MMPs have long been a focus of anticancer research, because they are up-regulated in many different tumors and might contribute to tumor growth and metastasis. Clinical trials using MMP inhibitors (MMPI), however, have been mostly disappointing. This can be partially attributed to the different timeframes of animal experiments compared to patient treatments: MMPs play a role mainly in early stage cancers, whereas most participants in clinical trials suffer from advanced-stage cancer [19]. As it
Collagenase-2 in innate immunity
It is not surprising that MMP-8 plays a prominent role in the development of inflammatory reactions, as it is stored, like MMP-9, as an inactive pro-enzyme in secondary granules of mature neutrophils. These neutrophils are the first inflammatory cell type to arrive at an inflammatory site, secreting their granular contents after stimulation. Thus, MMP-8 is present at the initial stage of an inflammatory reaction, and can therefore influence its outcome.
Since collagen type I is the predominant
Vascular diseases
An increasing amount of clinical data supports the notion that MMP-8 is involved in the development of atherosclerosis. In contrast to normal arteries, MMP-8 can be found in atherosclerotic lesions, specifically in macrophages, smooth muscle cells and endothelial cells. Interestingly, rupture prone plaques clearly displayed increased MMP-8 expression compared to stable plaques [35]. More recent studies have shown that vulnerable plaques also had an increased amount of activated MMP-8 [36], and
Conclusion
In this review we have given the reader an overview of the current state of knowledge concerning the role of MMP-8 in both inflammation and cancer progression. We have tried to show that MMP-8 is associated with a wide range of pathologies and might therefore be useful as a disease marker. More importantly, recent animal experiments also indicate that MMP-8 influences the course of many pathological processes, such as cancer metastasis and fibrosis, as well as innate immune responses and the
Acknowledgements
The authors wish to thank Dr. Amin Bredan for editing this review, as well as all investigators working in the field for their contributions. Research in the authors’ laboratory was supported by the Institute for the Promotion of Innovation through Science and Technology in Flanders (IWT-Vlaanderen) and the Interuniversity Attraction Poles Program of the Belgian Science Policy.
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