The importance of matrix metalloproteinase-3 in respiratory disorders

Abstract

The matrix metalloproteinases (MMPs) encompass a family of zinc-dependent endopeptidases that are secreted into the extracellular environment or remain bound to the cell surface. While MMPs were initially identified based on their ability to degrade collagen and other components of the extracellular matrix, recent studies indicate that their non-degradative functions are physiologically paramount. In particular, MMPs are now known to participate in diverse physiological processes that control key aspects of inflammatory and immune responses and neoplasia, in part by selective triggering of cellular signaling pathways via limited proteolytic processing of extracellular and membrane-associated proteins, including cytokines and cell surface receptors. Herein, we focus on the unique roles of MMP-3 (stromelysin-1) in acute lung injury and repair, pulmonary fibrosis, and lung cancer.

Keywords::

• acute lung injury
• acute respiratory distress syndrome
• epithelial mesenchymal transformation
• extracellular matrix
• lung cancer
• proteinase
• proteolytic processing
• pulmonary fibrosis
• signal transduction

Financial & competing interests disclosure

C Yamashita has received grant funding from the Canadian Institute of Health. D Radisky, R Zemans and G Downey have received grant funding from the National Institute of Health. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending or royalties.

No writing assistance was utilized in the production of this manuscript.

Key issues

• The matrix metalloproteinases (MMPs) are a family of enzymes with the ability to degrade components of the extracellular matrix (ECM). They play critical roles in tissue remodeling and wound repair.

• MMPs also participate in limited proteolytic processing, resulting in activation and inactivation of soluble and membrane-associated proteins, such as cytokines, growth factors and cell surface receptors. These functions may allow MMPs to paradoxically promote deposition of excess ECM.

• MMP-3 has been implicated in a range of pathological processes, including acute lung injury (ALI), pulmonary fibrosis and lung cancer.

• MMP-3 levels have been shown to be elevated in clinical specimens of patients with ALI, and in animal studies and mice genetically deficient in MMP-3 are protected in ALI models. This may be due to impaired neutrophil recruitment in MMP-3 knockout mice.

• MMP-3 may also promote breakdown of alveolar epithelial barriers and acute inflammatory responses, particularly in the setting of ventilator-induced lung injury: both mechanisms could contribute to the development of ALI.

• Genetic deletion of MMP-3 in mice confers protection from bleomycin-induced fibrosis, while transient overexpression of MMP-3 results in profibrotic responses in rat lungs. This likely occurs by induction of the Wnt-β-catenin pathway by MMP-3, resulting in epithelial-mesenchymal transition of lung alveolar epithelial cells.

• MMP-3-mediated degradation of the ECM enhances a profibrotic environment, which may affect the phenotype of fibroblasts and promote further deposition of ECM and fibrosis.

• MMP-3 may promote progression and metastasis of lung cancer by increasing expression of Rac1b, an isoform of Rac1, which has been implicated in various cancers through induction of reactive oxygen species and promotion of epithelial-mesenchymal transition.

• Targeting of MMP-3 may be a potential therapeutic strategy for the treatment of multiple respiratory disease processes, including ALI, fibrosis and lung cancer.

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