MMP-9 (also referred to as gelatinase B, 92 kDa type IV collagenase, 92 kDa gelatinase, and type
V collagenase) is secreted as a glycosylated proenzyme (6-8). Activation of the proenzyme involves
proteolytic removal of the N-terminal pro region, resulting in the 82 kDa active enzyme (9, 10).
Active human MMP-9 shares 72% and 74% amino acid sequence identity with mouse and rat
MMP-9, respectively. In addition to the zinc-binding site, the catalytic domain also contains three
contiguous fibronectin type II homology units responsible for binding gelatin (11). A proline-rich
hinge region links the catalytic domain to the C-terminal hemopexin-like domain. In vitro treatment
of the proenzyme with 4-aminophenylmercuric acetate (APMA) produces not only the active
enzyme but also a C-terminal truncated form with activity comparable to that of the active form
(12). MMP-9 degrades components of the ECM with high specific activity for denatured collagens
(gelatin). It can cleave native collagens of type III, IV, V, and XI, as well as Elastin, Nidogen-1, and
Vitronectin (2, 3). MMP-9 can also cleave a variety of chemokines and growth factors (e.g. IL-1 beta,
CXCL8/IL-8, CXCL7, CXCL4, CXCL1, Latent TGF-beta, membrane bound TNF-alpha, VEGF, and FGF basic),
Amyloid beta peptide, Substance P, and Myelin Basic Protein (3, 13-15). This action can increase or
decrease the biological activity of soluble factors and can also liberate them from association with
the ECM (16, 17). MMP-9 can also trigger signaling through various transmembrane proteins or
inhibit signaling by inducing their shedding from the cell surface (e.g. CD44, E-Cadherin, Integrins,
ICAM-1, and IL-2 R alpha ) (3, 18-20).
MMP-9 is produced by a variety of normal and transformed cells including neutrophils, monocytes,
macrophages, astrocytes, fibroblasts, osteoclasts, chondrocytes, keratinocytes, endothelial and
epithelial cells. It exerts physiological and pathological angiogenic and remodeling effects on the
vasculature (21-25). Activated neutrophils release proMMP-9 which is free of TIMP-1, allowing the
liberation of pro-angiogenic FGF-2 from the ECM (17). MMP-9 in complex with TIMP-1 does not
induce FGF-2 release (17). Neutrophil-derived MMP-9 exacerbates the inflammatory response, in
part by generating collagen-derived peptides that induce the release of additional neutrophil MMP9 (26). MMP-9 also plays a role in bone formation and remodeling (1, 21, 27), methamphetamineinduced behavioral sensitization and reward (28), the regulation of neuronal synapse remodeling
(29), trophoblast invasion during implantation (30), and the inactivation of Serpin alpha 1-Proteinase
Inhibitor (31). The shedding of adhesion proteins by MMP-9 has a direct effect on tumor cell
invasiveness (18-20).
Circulating levels of MMP-9 are increased in many inflammatory disorders including intraluminal
thrombus formation (32), atherosclerosis (33), Crohn's disease (34), hepatitis C virus infection (35),
colorectal cancer (36), and Duchenne muscular dystrophy (37). The ratio of MMP-9 to TIMP-1 is also
increased in multiple sclerosis serum (38) and cystic fibrosis sputum (39), but it is decreased in the
serum during cytomegalovirus infection (40). Levels of free MMP-9 and complexes of MMP-9 with
Lipocalin-2/NGAL are elevated in the urine of ovarian cancer and uterine tract infection patients,
respectively (41, 42).
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