Enzyme Catalysis and Regulation
A Key Role for Mast Cell Chymase in the Activation of Pro-matrix Metalloprotease-9 and Pro-matrix Metalloprotease-2*

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Chymases, serine proteases exclusively expressed by mast cells, have been implicated in various pathological conditions. However, the basis for these activities is not known, i.e. the in vivo substrate(s) for mast cell chymase has not been identified. In this study we show that mice lacking the chymase mouse mast cell protease 4 (mMCP-4) fail to process pro-matrix metalloprotease 9 (pro-MMP-9) to its active form in vivo, whereas both the pro and active form of MMP-9 was found in tissues of wild type mice. Moreover, the processing of pro-MMP-2 into active enzyme was markedly defective in mMCP-4 null animals. Histological analysis revealed an increase in collagen in the ear tissue of mMCP-4-deficient animals accompanied by increased ear thickness and a higher content of hydroxyproline. Furthermore, both lung and ear tissue from the knock-out animals showed a markedly increased staining for fibronectin. MMP-9 and MMP-2 are known to have a range of important activities, but the mechanisms for their activation in vivo have not been clarified previously. The present study thus indicates a key role for mast cell chymase in the regulation of pro-MMP-2 and -9 activities. Moreover, the results suggest an important role for mast cell chymase in regulating connective tissue homeostasis.

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This work was supported by grants from the AgriFunGen program at the Swedish University of Agricultural Sciences, the Swedish Research Council, Formas, and the King Gustaf V 80th Anniversary Fund. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

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Present address: Dept. of Molecular Biology and Biochemistry, Faculty of Sciences, University of Malaga, Campus de Teatinos, s/n 29071 Malaga, Spain.