Molecular Scissors: From Biomaterials Implant to Tissue Remodeling - Biologically Responsive Biomaterials for Tissue Engineering - page 19

2.2 Extracellular Matrix Tailoring by Speci fi c Means

Controlled interactions between ECM and mature differentiated cells may induce impor-
tant changes in cells' behavior following specific signaling pathways [ 25, 58, 67 ] . Matrix
tailoring supposes not only pure ECM dissection and cleavage for its main molecules but
also subtle changes in ECM composition, which may alter the activity of the growth
factors or of cells' surface receptors. In order for the essential biological processes to
develop, ECM must be degraded in a controlled manner in order to allow cell displacement
during embryonic development, tissue remodeling, and tissue repair [ 1, 85 ] . However, the
same process of ECM degradation, if exceeded by the impairment of natural inhibitors,
participates as innocent bystander or by active facilitator to growth, invasion, and metas-
tasis of malignant cells. These processes are directly mediated by Matrix Metalloproteinases
(MMPs), which we may consider to act as true molecular scissors for ECM.

2.3 Proteases and MMPs Family

All MMPs are included in the main class of proteases. These proteases include exo-
and endopeptidases (also called proteinases). These proteinases can be divided in
four classes according to the catalytic site and active center: serin/threonin protei-
nases, cysteine proteinases, aspartic proteinases, and metalloproteinases [ 20, 39, 71,
88 ]. Folding similarities are dividing metalloproteinases in clans while an evolu-
tionary classification divides them in families. In metalloproteinases class we may
include 8 clans and 40 families [ 121 ]. MMP members are included in the MB clan,
characterized by a specific three His residues from which the third is bound to the
Zn ion [ 24 ]. In this clan we can observe two major families (M12 and M10), each
with two subfamilies, astacins and reprolysins for the first family and seralysins and
matrixins (MMP) for the second. MMPs are gathered together in this subfamily of
zinc and calcium-containing endoproteases that have been traditionally character-
ized by their collective ability to degrade all components of the ECM [ 121 ] . These
enzymes are supposed to regulate the homeostasis in various tissues under the direct
control of tissue inhibitor of metalloproteinases (TIMPs), which bind to and inhibit
the activity of MMPs [ 19, 43 ]. Accordingly, an imbalance between MMPs and
TIMPs can lead to a variety of pathological states, such as metastasis of cancer [ 29 ] ,
or diseases including rheumatoid arthritis and multiple sclerosis [ 32 ] . At least 28
members of this enzyme family, which demonstrate significant sequence homology,
have been reported [ 19, 22, 87 ]. Following functional criteria, they can be classified
as collagenases (MMP-1, -8, -13, and -18), gelatinases (MMP-2 and -9), stromelysins
(MMP-3, -10, and -11), matrilysins (MMP-7 and -26), enamelysin (MMP-20), met-
alloelastase (MMP-12), and membrane-type MMPs (MMP-14, -15, -16, -17, -24,
and -25) [ 121 ]. Part of the newly discovered MMPs (after 1996) remain in a separate
group, called “others” (MMP-19, -21, -23, -27, -28) while classification undergoes