Matrix metalloproteinase (MMP)-7 activates MMP-8 but not MMP-13.
Matrix Metalloproteinases (MMPs) are a class of zinc-dependent enzymes that degrade extracellular matrix components, particularly collagen. MMPs have been implicated in a diverse list of pathological processes, including cancer and cardiovascular disease. Recent efforts to bring MMP inhibitors to clinical trials, however, have proved disappointing. These failures are attributed, in part, to the non-selective nature of current inhibitors. The possibility also exists, however, that inhibition of a particular MMP type will lead to feedback accumulation of parallel MMP members. MMP-7, also known as matrilysin, has a broad list of substrates, including denatured collagen and other MMPs involved in the collagenolytic pathway, namely MMP-1, MMP-2, and MMP-9. Whether the additional collagenases, MMP-8 and MMP-13, are also activated by MMP-7 has not been explored. We show here that recombinant active MMP-7 was able to process MMP-8 to its active form in vitro, but did not activate MMP-13. In the left ventricles of mice lacking the MMP-7 gene, MMP-8 levels increased while MMP-13 levels decreased in vivo. The switch in MMP profile was not accompanied by a change in left ventricular dimensions or wall thickness. Together, these data suggest that MMP-8 is an in vivo substrate of MMP-7, and that the accumulation of pro-MMP-8 in the absence of MMP-7 downregulates pro-MMP-13 levels in order to maintain baseline collagenolytic function. The interplay between MMP-8 and MMP-13 suggest that these MMPs may play reciprocal roles. The design of selective MMP inhibitors, therefore, must take into consideration changes in parallel MMP types as a potential compensatory mechanism.
Dozier
S
S
Cardiology Division, Department of Medicine, The University of Texas Health Science Center at San Antonio, 7703 Floyd Curl Drive, Mail Code 7872, San Antonio, TX 78229-3900, USA.
Escobar
G P
GP
Lindsey
M L
ML
D000818:Animals; D004452:Echocardiography; D004789:Enzyme Activation; D005260:Female; D008297:Male; D053509:Matrix Metalloproteinase 13 / Q000378:metabolism; D020783:Matrix Metalloproteinase 7 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D020784:Matrix Metalloproteinase 8 / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009206:Myocardium / Q000201:enzymology; D013379:Substrate Specificity
D053509:Matrix Metalloproteinase 13; D020783:Matrix Metalloproteinase 7; D020784:Matrix Metalloproteinase 8