MMP-12 activates protease-activated receptor-1, upregulates placenta growth factor, and leads to pulmonary emphysema

How does the coagulation protease thrombin regulate cellular behaviour? The protease-activated receptors (PARs) provide one answer. In concert with the coagulation cascade, these receptors provide an elegant mechanism linking mechanical information in the form of tissue injury or vascular leakage to cellular responses. Roles for PARs are beginning to emerge in haemostasis and thrombosis, inflammation, and perhaps even blood vessel development.

Protease-activated receptors (PARs) are a unique class of G protein-coupled receptors that play critical roles in thrombosis, inflammation, and vascular biology. PAR1 is proposed to be involved in the invasive and metastatic processes of various cancers. However, the protease responsible for activating the proinvasive functions of PAR1 remains to be identified. Here, we show that expression of PAR1 is both required and sufficient to promote growth and invasion of breast carcinoma cells in a xenograft model. Further, we show that the matrix metalloprotease, MMP-1, functions as a protease agonist of PAR1 cleaving the receptor at the proper site to generate PAR1-dependent Ca2+ signals and migration. MMP-1 activity is derived from fibroblasts and is absent from the breast cancer cells. These results demonstrate that MMP-1 in the stromal-tumor microenvironment can alter the behavior of cancer cells through PAR1 to promote cell migration and invasion.

To determine which proteinases are responsible for the lung destruction characteristic of pulmonary emphysema, macrophage elastase-deficient (MME-/-) mice were subjected to cigarette smoke. In contrast to wild-type mice, MME-/- mice did not have increased numbers of macrophages in their lungs and did not develop emphysema in response to long-term exposure to cigarette smoke. Smoke-exposed MME-/- mice that received monthly intratracheal instillations of monocyte chemoattractant protein-1 showed accumulation of alveolar macrophages but did not develop air space enlargement. Thus, macrophage elastase is probably sufficient for the development of emphysema that results from chronic inhalation of cigarette smoke.