Molecular Scissors: From Biomaterials Implant to Tissue Remodeling - Biologically Responsive Biomaterials for Tissue Engineering - page 29

domain than for the hemopexinic domain of MMP. Regarding the activation
mechanism, these data correspond to the well-known experimental results [ 7, 31,
77 ], that sustain that initially; TIMP2 forms an activation complex with the
hemopexinic domain in MMP2.
Even if has a higher affinity for TIMP2, the catalytic domain cannot bind it while
the specific binding site is inactive in the pro-form of the enzyme. Following MMP2
activation and removal of the pro-domain of the enzyme, the catalytic site becomes
available and the favorable free binding energy will induce either the substrate binding
or the natural inhibitor TIMP2. We have confirmed that MMP2 can consecutively
bind two TIMP2 molecules, one for the activation complex at the hemopexinic domain
level and the other at the catalytic site, inducing inhibition. For the MMP9-TIMP2
complex, the affinity for the hemopexinic and the catalytic site was almost the same.
Thus, the activation-inhibition model in this triad could be [ 91 ] : MMP2 together
with TIMP2 and MT-MMP1 forms an activation complex that activates MMP2; the
activated MMP2 attacks the specific substrate. At the same time TIMP2 will inhibit
MMP9 at the catalytic site while the hemopexinic site is already coupled with
TIMP1 that participates to its activation.

2.6 MMPs in Wound Repair

MMPs participate to all wound repair steps following biomaterial implantation
(Fig. 2.9 ) [ 34, 73 ] .
Inflammation step is mediated by cytokines and chemokines incoming from resi-
dent cells in the tissue to which implantation is addressed (epithelial or endothelial
cells, fibroblasts). MMPs can activate the inflammatory mediators at cell surface
either by direct processing (cleavage of a pro-domain) or even by degradation, thus
inhibiting pro-inflammatory signals. MMPs are also able to cleave molecular
domains of the intercellular or cell-matrix junctions in epithelia in order to promote
re-epithelization. Moreover, MMPs are involved in scar tissue remodeling either by
direct proteolytic cleavage of collagen molecules or indirect, by influencing cell
behavior. ECM processing is complete at the end of wound repair process but is also
involved in regulation of the inflammatory process. MMPs are playing key regula-
tion factor roles regarding multiple processes in tissue repair [ 52, 98 ] .
MMPs are also playing important roles in inflammatory processes. As we
have already emphasized, inflammation is one of the first processes at the bioma-
terial implant site. Inflammation processes are associated to leukocyte influx and
activation and are influenced by antimicrobial peptides, lipid mediators, recep-
tors, chemokines, and cytokines, fragments derived from ECM. Production and
activation of these factors is controlled by effectors that include MMPs. Specific
MMPs derived from epithelial cells are regulating numerous steps during
inflammation, as leukocyte trans-epithelial migration, activity, and distribution of
chemokines [ 21 ]. Inflammatory cells are expressing MMPs as all other epithelial