Riding the metalloproteinase roller coaster

Abstract

To many of us in the field, working on matrix metalloproteinases (MMPs) has felt like riding a roller coaster, traveling through times of both excitement and despair. I was fortunate to join the ride when it was a mere carousel of three activities thought to target the proteins that comprise the extracellular matrix (ECM). New technologies brought the thrills of discovery as we uncovered specific proteinase genes and defined specialized activities in different cellular processes. The MMPs and the sister families of "a disintegrin and metalloproteinase" (ADAMs), ADAMs with thrombospondin domains (ADAM-TS), and Astacins are now recognized as key signaling "scissors" that drive rapid changes in a plethora of cellular pathways. My many excellent colleagues and collaborators and I were enthused to contribute to the early development of the field and continue to be amazed at its growth and sophistication. In contrast, the hype and failure of early inhibitor discovery have dogged our standing with the pharmaceutical industry and grant-giving bodies. However, the true believers have kept going, and knowledge of particular functions of MMPs and their contributions to disease progression has progressed. Recognition of the strategic importance of proteinase function should inspire more work harnessing new technologies such as imaging, proteomics, and gene editing to generate a more precise understanding of individual situations. New approaches to inhibitor design and assessment are possible, and the consequent ability to precisely abrogate specific MMP activity could contribute to the fight against a number of pathologies with unmet needs. What a ride it could be!

Metalloproteinases and their roles in human cancer

“…MMP and ADAM family members contribute to many physiological and pathological processes by mediating cellular proliferation, migration, invasion, differentiation, apoptosis, inflammation, and angiogenesis by degrading a variety of ECM proteins including Type I and IV collagens, laminin, fibronectin, fibrinogen, and proteoglycans (Roy et al, , ; Murphy, , ; Murphy and Nagase, ; Hadler‐Olsen et al, ; Bonnans et al, ; Yang et al, ; Das et al, ). Proteolysis of basement membrane components is directly associated with cancer cell invasion by cleavage and release of cryptic peptides or neoepitopes that alter cell‐matrix interactions and are involved in signaling between basement membrane and cancer cells (Schenk and Quaranta, ).…”

Current insights into matrix metalloproteinases and glioma progression: transcending the degradation boundary

“…An almost uncharted territory in the brain for MMP enthusiasts are the unique mechanical properties of the brain parenchyma and the complicated changes that take place with the ECM during brain diseases. 210 Much of what is known about MMP structure/function comes from studies in arthritis, 10 and while Young's modulus of brain tissue is quite different from bone, we believe there is a vast amount of information concerning mechanotransduction regulation of MMPs in gliomas. Little is known about the influence of fluid dynamics and sheer stress on temporal and spatial MMP functions in gliomas.…”

“…mRNA-expression levels in control tissue (ie, non-pathological tissue obtained during surgical resection of epilepsy patients), grade III anaplastic astrocytoma, and GBM were assessed using custom-designed TaqMan lowdensity arrays containing primer and probe sets for 384 proteases. Transcript levels of MMPs 1,2,7,9,10,11,12,14,19, and 21 were significantly increased in GBM relative to control. Notably, MMP19 was also increased in anaplastic astrocytoma relative to control, but decreased in grade IV GBM relative to grade III anaplastic gliomas.…”

“…Recent reports on the multifunctionality of MMPs, including intracellular nonproteolytic actions in various cell types, are intriguing 8,9 and pave the way for new avenues of MMP research built upon an already solid foundation. 10 This review provides an overview on the structure/function and regulation of MMPs, but will primarily focus on relating data on MMP gene expression obtained from publicly available data sets and our reverse-transcription quantitative polymerase chain reaction (RT-qPCR) data demonstrating unique glioma-expression patterns of MMPs to proteolytic and recently identified novel, nonproteolytic MMP functions. Although previous MMP-inhibitory trials were largely unsuccessful, 11 these recently identified functions not only open up new research avenues but may also lead to the identification of potentially targetable MMPs for therapeutics.…”

Lipidmediatoren und ihre Rolle bei Entzündungen und Allergien

“…Natürlich sind deshalb mittlerweile Metalloproteinasen-Inhibitoren auch zum interessanten Forschungsthema für die Pharmaindustrie geworden, das jedoch nach anfänglichem Hype in letzter Zeit wegen zahlreicher Fehlschläge an Attraktivität eingebüßt hat. Deshalb wird deren Erforschung aktuell mit einem Ritt auf der "Achterbahn" verglichen (Murphy 2017).…”