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Sci Rep. 2019 Mar 13;9(1):4340. doi: 10.1038/s41598-019-40983-y.

Identification of fibrinogen as a natural inhibitor of MMP-2.

Author information

1
Department of Biochemistry, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB, T6G 2H7, Canada.
2
Biotechnology Laboratory, Study Center for Research and Biological Evaluations, Institute of Pharmacy and Foods, University of Havana, Havana, P.O. Box 13600, Cuba.
3
Department of Medicine, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB, T6G 2H7, Canada.
4
Departments of Pediatrics, Division of Medical Genetics and Pediatrics, University of Utah, Salt Lake City, UT, 84108, USA.
5
Department of Biochemistry, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB, T6G 2H7, Canada. cf2@ualberta.ca.

Abstract

Non-genetic MMP-2 insufficiency is a relatively unexplored condition which could be induced by pathological overexpression of endogenous MMP-2 inhibitors such as TIMPs and/or the acute phase reactant alpha-2-macroglobulin. Here, we investigate the hypothesis that human fibrinogen (FBG) - an acute phase reactant - inhibits human MMP-2. Following an unexpected observation where sera from human donors including arthritis patients with increased levels of serum FBG exhibited reduced binding of serum proMMP-2 to gelatin, we found that human FBG (0 to 3.6 mg/mL i.e., 0 to 10.6 μM) concentration-dependently inhibited human proMMP-2 and MMP2 from binding to gelatin. Moreover, at normal physiological concentrations, FBG (5.29-11.8 μM) concentration-dependently inhibited (40-70% inhibition) the cleavage of fluorescein-conjugated gelatin by MMP-2, but not MMP-9. Indicative of a mixed-type (combination of competitive and non-competitive) inhibition mechanism, FBG reduced the Vmax (24.9 ± 0.7 min-1 to 17.7 ± 0.9 min-1, P < 0.05) and increased the Michaelis-Menten constant KM (204 ± 6 nM to 478 ± 50 nM, P < 0.05) for the reaction of MMP-2 cleavage of fluorescein-conjugated gelatin. In silico analyses and studies of FBG neutralization with anti-FBG antibodies implicated the domains D and E of FBG in the inhibition of MMP-2. In conclusion, FBG is a natural selective MMP-2 inhibitor, whose pathological elevation could lead to MMP-2 insufficiency in humans.

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