A key role for mast cell chymase in the activation of pro-matrix metalloprotease-9 and pro-matrix metalloprotease-2.
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.
Tchougounova
Elena
E
Swedish University of Agricultural Sciences, Department of Molecular Biosciences, BMC, Box 575, 75123 Uppsala, Sweden.
Lundequist
Anders
A
Fajardo
Ignacio
I
Winberg
Jan-Olof
JO
Abrink
Magnus
M
Pejler
Gunnar
G
D000818:Animals; D053818:Chymases; D017364:Collagenases / Q000378:metabolism*; D003238:Connective Tissue / Q000201:enzymology; D004789:Enzyme Activation; D004792:Enzyme Precursors / Q000378:metabolism*; D018093:Gelatinases / Q000378:metabolism*; D008168:Lung / Q000201:enzymology; D020780:Matrix Metalloproteinase 9; D008666:Metalloendopeptidases / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D009206:Myocardium / Q000201:enzymology; D011499:Protein Processing, Post-Translational; D012697:Serine Endopeptidases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*
D004792:Enzyme Precursors; D012697:Serine Endopeptidases; C066932:mast cell protease 4; D053818:Chymases; D017364:Collagenases; D018093:Gelatinases; D008666:Metalloendopeptidases; C120487:pro-matrix metalloproteinase 9; C069860:progelatinase; D020780:Matrix Metalloproteinase 9