Mouse matrix metalloprotease-1a (Mmp1a) gives new insight into MMP function.

Matrix metalloprotease-1 (MMP1) has been implicated in many human disease processes, however the lack of a well characterized murine homologue has significantly limited the study of MMP1 and the development of MMP-targeted therapeutics. The discovery of murine Mmp1a in 2001, the functional mouse homologue of MMP1, offers a valuable tool for modeling MMP1-mediated processes in mice. Variation in physiologic expression levels of Mmp1a in mice as compared to MMP1 in humans highlights the importance of understanding the similarities and differences between the homologues. Recent studies have demonstrated tumor growth-, invasion-, and angiogenesis-promoting functions of Mmp1a in lung cancer models, consistent with the analogous functions observed for human MMP1. Biochemical investigations have shown that point mutations in the pro-domain of mouse Mmp1a weaken docking between the pro- and catalytic domains, generating an unstable zymogen primed for activation. The difficulty to effectively maintain Mmp1a in the zymogen form may account for the tight control of Mmp1a expression and reduced expression in normal tissue as compared to inflammatory states or cancer. This discovery raises important questions about the activation mechanisms and regulation of the MMP family in general.