Matrix Metalloproteinases and the Issue of Ortholog Equivalence


I am currently working on a new book which is intended to describe macromolecules in the extravascular space.   This is all new territory for me.  Thus I learned that matrix metalloproteinases (MMPs) are numbered 1-28, only 24 human enzymes are described.  I am not clear as to how the nomenclature was established but it does not appear that the thought leaders in this field required meetings in nice venues  as was required for coagulation proteins.   I also learned that most have been identified by the use of PCR cloning  establishing homology with established MMPs(1).  In addition, while in vitro studies have identified substrates,  there is little in vivo evidence for a specific function.  Finally, much work is done in mice with the assumption that there is ortholog equivalence (also found that ortholog is not in the Oxford Dictionary of the English Language).   Ortholog functional non-equivalence has been known for some time (2) and I found several more recent examples from various systems (3-5), a recent review (6) and comment in the lay press (7).


A striking example of functional non-equivalence of orthologous systems is provided by a recent study by Fleetwood and coworkers (8) on the role of urokinase plasminogen activator as a major factor in macrophage degradation of matrix.   These investigators demonstrate that urokinase plasminogen activator bound to urokinase plasminogen receptor on the macrophage surface activates plasminogen to plasmin which, in the mouse system, activates MMP-9 which then degrades matrix.   This conclusion is based on the ability of, GM6001, an inhibitor of MMPs which inhibited the murine system in the degradation of a 3D Matrigel® barrier but had no effect on a human system.  These results suggest the involvement of another protease in the human system.  These results have great importance in the development of inhibitors of MMPs; such inhibitors are of interest in the treatment of various tumors (9).  Getting back to one of the points above, it is clear that studies with matrix metalloproteinases must involve human systems to validate observations in murine systems AND a better identification of physiological interactions and in vivo in human systems.

References


1.  Cossins, J., Dudgeon, T.J., Catlin, G., et al., Identification of MMP-18, a putative novel human matrix metalloproteinase, Biochem.Biophys.Res.Commun. 228, 494-498, 1996.
2. Lind, D.E., Bradley, M.L., Gunz, F.W., and Vincent, P.C., The non-equivalence of mouse and human marrow culture in the assay of granulopoietic stimulatory factors,  J.Cell.Physiol. 83, 35-42, 1974.
3.  Svennson, P.,Blasing, O.E., and Westhoff, P., Evolution of the enzymatic characterization of C4 phosphoenolpyruvate carboxylase--a comparison of the orthologous PPCA phosphoenolpyruvate carboxylases of Flaveria trinerva (C4) and Flaveria pringlei (C3), Eur.J.Biochem. 246, 452-460, 1997.
4. Antcheva, N., Boniotto, M., Zeleszetsky, I., et al., Effects of positively selected sequence variations in human and Macaca fascicularis β-defensins 2 on antimicrobial activity, Antimicrob.Agents Chemother. 48, 685-688, 2004.
5.  Gao, B., Peigneur, S., Dalziel, J., et al., Molecular divergence of the orthologous scorpion toxins affecting potassium channels, Comp.Biochem.Physiol.A Mol.Integr.Physiol. 159,  313-321, 2011.
6.  Mestas, J. and Hughes, C.C.W., Of mice and not men: Differences between mouse and human immunology, J.Immunol. 172, 2731-2738, 2004.
7.  Kolata, G.,  Mice fall short as test subjects for some humans' deadly ills, New York Times, February 11, 2013.
8.  Fleetwood, A.J., Achuthan, A., Schultz, H., et al., Urokinase plasminogen activator is a central regulator of macrophage three-dimensional invasion, matrix degradation, and adhesion, J.Immunol. 192, 3540-3547, 2014.
9.  Dufour, A. and Overall, C.M., Missing the target: matrix metalloproteinase antitargets in inflammation and cancer, Trends Pharmcol.Sci. 34, 233-242, 2013.