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1.4.2 Elastin
Elastin is a remarkably durable ECM polymer, but in chronic inflammatory
conditions, such as emphysema and aneurysm formation, it is degraded leading
to severe consequences. Studies with mouse models have implicated macrophage-
derived MMP9 and MMP12 as the destructive elastases in these conditions (Curci
et al. 1998 ; Hautamaki et al. 1997 ; Houghton et al. 2006 ; Longo et al. 2002 ;Pyo
et al. 2000 ). Surprisingly, neither MMP9 nor MMP12 released by macrophages is
effective at degrading elastin in cell-based models (Filippov et al. 2003 ). Despite
this concern, the data strongly indicate that excess production of certain MMPs, as
occurs in nonresolving inflammation, does contribute to elastin breakdown.
1.4.3 Basement Membrane
As discussed extensively in Chap. 7, cancer cells break down basement membrane
during invasion and metastasis. Although this process is thought to be mediated by
MMPs, typically MMP2 and MMP9, the specific enzymes responsible for basement
membrane dissolution have not been demonstrated. MMP2 and MMP9 were initi-
ally called type IV collagenases because they could degrade this abundant basement
membrane component in vitro (Collier et al. 1988 ; Wilhelm et al. 1989 ). However,
this concept has been challenged (if not, in fact, debunked) by data, largely negative
data, with genetically modified mice (Parks et al. 2004 ; Stetler-Stevenson and Yu
2001 ). Furthermore, as thoroughly discussed and referenced in a recent review
(Rowe and Weiss 2008 ), several studies found that MMP2 and MMP9 are actually
weak type IV collagenases, and no basement membrane defects have been reported
in mice lacking either or both of these proteinases. Although the lack of basement
membrane effects can be attributed to redundancy or compensation, the fact
that Mmp2 -/- and Mmp9 -/- mice do reveal distinct, nonoverlapping phenotypes
in other processes (Cauwe et al. 2007 ; Parks et al. 2004 ) argues that these MMPs
evolved to carry out specific functions, an argument, we believe, that can be made
for all MMPs.
1.5 Silencing MMP Activity
1.5.1 TIMPs
As for all secreted proteinases, the catalytic activity of MMPs is regulated at four
points: gene expression, compartmentalization (i.e., pericellular accumulation of
enzyme), proenzyme (or zymogen) activation, and enzyme inactivation. MMP
activity is further controlled by substrate availability and affinity. TIMPs comprise
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