Synovial procollagenase activation by human mast cell tryptase dependence upon matrix metalloproteinase 3 activation.
Mast cells have been implicated in the pathogenesis of the matrix degradation observed in the cartilaginous and osseous structures of the rheumatoid joint. We previously reported that human mast cell tryptase, a 134-kD granule-associated neutral protease, is present in rheumatoid synovium and can activate collagenase in crude culture medium in vitro. the present study attempts to depict the precise mechanism of this activation. To express full activation of latent collagenase, matrix metalloproteinase 3 (MMP-3) or stromelysin, can be activated by tryptase in a time and dose-dependent manner. Tryptase was not capable of generating active collagenase in the crude media from cultured rheumatoid synoviocytes depleted of proMMP-3 by immunoadsorption. In addition, the function of the tissue inhibitor of metalloproteinases (TIMP) was not altered by tryptase, and SDS-PAGE analysis revealed no degradation of TIMP by tryptase. The tryptase dependent activation of synoviocyte procollagenase thereby appears to be entirely dependent upon its ability to activate proMMP-3.
Gruber
B L
BL
Division of Allergy, Rheumatology and Clinical Immunology, Veterans Administration, Northport, New York 11768.
Marchese
M J
MJ
Suzuki
K
K
Schwartz
L B
LB
Okada
Y
Y
Nagase
H
H
Ramamurthy
N S
NS
D015153:Blotting, Western; D003094:Collagen / Q000378:metabolism; D017364:Collagenases; D004789:Enzyme Activation / Q000187:drug effects; D004792:Enzyme Precursors / Q000378:metabolism*; D006023:Glycoproteins / Q000494:pharmacology; D006801:Humans; D008407:Mast Cells / Q000201:enzymology*; D019278:Matrix Metalloproteinase 3; D008666:Metalloendopeptidases / Q000378:metabolism*; D003012:Microbial Collagenase / Q000378:metabolism*; D010447:Peptide Hydrolases / Q000494:pharmacology*; D013583:Synovial Membrane / Q000201:enzymology*; D019714:Tissue Inhibitor of Metalloproteinases
D004792:Enzyme Precursors; D006023:Glycoproteins; D019714:Tissue Inhibitor of Metalloproteinases; D003094:Collagen; D010447:Peptide Hydrolases; C023073:tosylarginine methyl ester hydrolase; D017364:Collagenases; D008666:Metalloendopeptidases; C022440:procollagenase; D019278:Matrix Metalloproteinase 3; D003012:Microbial Collagenase