Biology Reference
In-Depth Information
the TIMPs, of which there are four members. The TIMPs are 20-29-kDa reversible
inhibitors of MMPs whose activity mostly arises from evenly spaced cysteine
residues within the N-terminal domain of the protein (Gomez et al.
1997
). The
individual members of the TIMP family differ in their ability to inhibit specific
MMPs. For the most part, TIMP2 and -3 display preferential activity against the
membrane-bound MMPs, while TIMP1 inhibits the secreted MMPs, although there
are exceptions.
Based upon simple in vitro assays of catalysis, six members of the MMP family
(MMP2, -3, -7, -9, -10, and -12) have been shown to cleave elastin (see Table
9.1
),
although the ability of MMP3 and -10 has been questioned. Pathophysiological roles
for these enzymes in elastic fiber degradation appear to be a function of the source of
enzyme expression. Macrophage-derived MMPs (9 and 12) are important in elastic
fiber degradation occurring within lung whereas MMP2, -3, and -10 are most
commonly implicated in vascular elastin degradation. However, MMP9 and -12
have been implicated in both COPD/emphysema and AAA, to varying degrees.
MMP2 (gelatinase A or 72-kDa gelatinase) is a simple hemopexin-type MMP
with the addition of a gelatin-binding domain. It can be elaborated from various
sources but is primarily fibroblast or mesenchymal cell-derived. MMP2 displays a
broad substrate specificity including all structures of the basement membrane and is
unique in its ability to degrade both elastin and fibrillar collagens. The predominant
pathophysiological role for MMP2-mediated elastic fiber degradation is in the
formation and progression of AAA.
MMP2
/
mice are protected from the devel-
opment of aortic aneurysms in the CaCl
2
infusion model (Longo et al.
2002
). The
contribution of MMP2 was purely mesenchymal cell-derived in AAA formation as
bone marrow transfer experiments failed to reverse the phenotype. Furthermore,
MMP2 has been identified in clinical AAA specimens using IHC, giving credence
to a role for the enzyme in human disease (Goodall et al.
2001
).
MMP3 (stromelysin-1) and -10 (stromelysin-2) have also been implicated aneu-
rysm formation. Polymorphisms in each of these genes confer increased risk of
AAA, although in different populations (Yoon et al.
1999
; Ogata et al.
2005
).
Expectedly,
MMP3
/
mice are protected in experimental models of AAA (Silence
et al.
2001
). The TIMPs are also required in this setting, as their deletion results in
increased aortic diameter upon injury (Silence et al.
2002
). Similar to the findings
for MMP2, the effects of MMP3 (in this model) are mesenchymal cell- and not
inflammatory cell-derived.
The individual contributions of macrophage-derived MMPs to elastolysis have
been difficult to tease apart. Both macrophage-derived MMP9 and -12 play signifi-
cant roles in elastolysis in vivo. MMP9 contributes to aneurysm formation in both
the elastase and CaCl
2
models of AAA formation (Pyo et al.
2000
; Longo et al.
2002
). Bone marrow transfer studies have proved that the contribution of MMP9 in
this setting is solely macrophage-derived. The role of MMP12 in AAA remains
unclear. Initial studies using
MMP12
/
mice in the elastase model of AAA failed
to demonstrate a role for this elastase (Pyo et al.
2000
). A subsequent study employ-
ing the CaCl
2
model, however, suggested that MMP12 is required for macrophage
accumulation in AAA (Longo et al.
2005
), consistent with EF-mediated monocyte
