Extracellular matrix (ECM) remodeling is involved in normal physiological processes,
such as embryonic development, reproduction, proliferation, cell motility and adhesion,
wound healing, angiogenesis, as well as in disease processes, such as arthritis and
metastasis. Matrix metalloproteinases (MMPs) are a family of proteolytic enzymes that
degrade various components of the ECM in these processes. MMPs are divided into six
groups, depending on their structure and substrate specificity: 1) Collagenases, such as
MMP-1 and MMP-13, 2)
Gelatinases, such as Gelatinase-A (MMP-2) and Gelatinase-B
(MMP-9), 3) Stromelysins, such as
Stromelysin-1 (MMP-3) and
Stromelysin-2 (MMP-10), 4) Matrilysins, such as
Matrilysin (MMP-7), 5) Membrane-type MMPs (MT-MMPs), such as
the type-I transmembrane proteins MMP-14,
MMP-15, and MMP-16,. 6) Other
MMPs, such as MMP-12 .
Endogenous tissue inhibitors of metalloproteinases (TIMPs), such as
TIMP1, TIMP2 and
TIMP3, reduce excessive proteolytic ECM degradation by MMPs.
The balance between activated MMPs and TIMPs controls the extent of ECM remodeling , .
MMPs are excreted by various connective tissues and pro-inflammatory cells including
fibroblasts, osteoblasts, endothelial cells, macrophages, neutrophils, and lymphocytes
. These enzymes are expressed as zymogens and are subsequently processed
by other MMPs or other classes of proteolytic enzymes .
Stromelysin-1 activates a number of proMMPs, including
the processing of MMP-1, MMP-13
and Matrilysin (MMP-7) into fully active proteinases . Stromelysin-1 also degrades ECM proteins, e.g.,
Secreted protein acidic cysteine-rich (Osteonectin), as well
as the components of basement membranes, such as Laminin 1
, , .
Stromelysin-2 is involved in the degradation of ECM
proteins involved in wound repair, such as Collagen I,
Collagen III, and Nidogen.
Furthermore, it can activate other MMPs, such as MMP-1
MMP-2 is not activated by general proteinases, but by
membrane MMPs, such as MMP-14,
MMP-15, and MMP-16 on the cell
Kallikrein serine protease 1 (Kallikrein 1)
activates latent MMP-9 involved in the
degradation of ECM proteins, such as Collagen I,
Collagen II, Collagen
IV, and Versican , , , .
Plasminogen activator urokinase (PLAU) plays a pivotal
role in the regulation of cell adhesion and migration during tissue remodeling. It
activates intracellular signaling upon binding to certain receptors on the cell surface.
Kallikrein-related peptidase 2 (Kallikrein 2)
can cleave PLAU to initiate its proteolytic
cascade . PLAU and Plasminogen activator
tissue (PLAT) are important components of the extracellular
protease system that specifically converts zymogen
Plasminogen into Plasmin,
the major fibrinolytic protease that is characterized by wide substrate
Plasmin directly degrades ECM proteins, such as
Fibronectin . It also activates a number of
MMPs, including MMP-1 and
MMP-13, that degrade the ECM proteins and the components of
the basal membrane, e.g., Collagen I, Collagen
IV, and Vitronectin , , , , , , , , , , , .
The proteolytic activity of Plasmin is regulated by
plasminogen activator inhibitors, such as Serpin peptidase inhibitor
(PAI1) and Serpin peptidase inhibitor member 2
(SERPINE2) that bind covalently to
PLAU and PLAT and inhibit their
catalytic activity , , , .
In addition to the proteolytic function, the tissue-type
PLAU plays an important role in the cell migration and
tissue remodeling. It binds to its receptor PLAUR and
mediates a variety of functions involved in vascular homeostasis, inflammation and tissue
Kallikrein 2 and Kallikrein-related peptidase 3
(Kallikrein 3) also cleave Insulin-like growth factor
binding protein 4 (IBP4). IBP4
fragments generated by kallikreins lose binding capacity to Insulin-like growth factors 1
and 2 (IGF-1 and IGF-2),
thereby increasing bioavailability of IGF-1 and
IGF-2. The latter two activate
IGF-1 receptor that is involved in the signaling implicated
with cell growth, proliferation and survival , .
Cell surface heparan sulfate proteoglycan CD44 recruits
proteolytically active Matrilysin (MMP-7) and precursor of
Heparin-binding EGF-like growth factor (HB-EGF) to form a
complex on the cell surface. Matrilysin (MMP-7) cleaves the
membrane-bound HB-EGF precursor, thus releasing active
HB-EGF. The latter then
activates its receptors, Epidermal growth factor receptor
(EGFR) and v-Erb-a erythroblastic leukemia viral oncogene
homolog 4 (ErbB4), thereby leading to cell proliferation,
cell survival and tissue remodeling , .
ECM components regulate cell motility and adhesion in response to the external
environmental processes, such as ECM remodeling . For example,
Collagen IV, the component of the basement membrane, binds
to Alpha-1/beta-1 integrin. Fibronectin binds to
Alpha-5/beta-1 integrin. This induces both cell adhesion,
and intracellular signaling , , , , , , .
PLAUR binds to Alpha-5/beta-1
integrin and alters its conformation to promote ligand-binding affinity
Cell surface heparan sulfate proteoglycans, CD44 and Syndecan-2,
bind ECM chondroitin sulfate proteoglycan
Versican and ECM protein Laminin, alpha 4
(LAMA4), respectively. CD44 and Syndecan-2
are implicated in the formation of a direct link between ECM and cortical
cytoplasm via association with the actin cytoskeleton binding proteins
Ezrin and Moesin , , , , , .
The action of MMPs is not restricted to degradation of the extracellular matrix; these
proteases can modify many non-matrix substrates, such as cytokines and chemokines. For
example, MMP-9 potentiates Interleukin-8
(IL-8) activity by aminoterminal processing.
IL-8 signaling via Interleukin 8 receptor alpha
(IL8RA) leads to the activation of neutrophils and
chemotaxis , .
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