Biology Reference
In-Depth Information
tissues, or with notable exceptions; their production and activity are at nearly
undetectable levels. In contrast, some level of MMP expression is seen in any
repair or remodeling process and in any diseased or inflamed tissue. Although the
qualitative patterns and quantitative levels of MMPs vary among tissues, dis-
eases, tumors, inflammatory conditions, and cell lines, a reasonably safe general-
ization is that activated cells express MMPs. Overall, it appears that the MMP
family expanded and evolved to function in the host response to environmental
stress. Supporting this idea, knockout of many genes whose products function
primarily in immunity also does not lead to developmental phenotypes. A key
exception to this generalization is MMP14 and to a lesser extent MMP13.
Mice lacking this proteinase suffer from extensive bony defects and die some
weeks after birth, and these severe phenotypes arise due to impaired collagen
turnover (Holmbeck et al.
1999
; Holmbeck et al.
2004
;Zhouetal.
2000
), as
would be expected when ECM metabolism is altered. Similar to
Mmp14
/
mice,
Mmp13
-/-
mice reveal defects in endochondral bone formation which point
clearly to an inability to remodel type II collagen (Inada et al.
2004
; Stickens
et al.
2004
). Although mice deficient in either MMP2, 9, 12, 13, or 20 have
permanent tissue defects, most are not severe and do not grossly affect fertility,
growth, or lifespan.
1.3.4
Is the Lack of Overt ECM Phenotypes Is Due
to Compensation or Redundancy?
This is a common assumption, but one that is not supported by data. In vivo
evidence for compensation among MMPs, that is, the activity of one MMP making
up for the loss of another, is lacking (Parks et al.
2004
; Zeisberg et al.
2006
).
Although increased expression of MMP3 and MMP10 is seen in the uteri of some
Mmp7
-/-
mice (Rudolph-Owen et al.
1997
), these two MMPs are expressed in
compartments distinct from where MMP7 is produced. Because MMP7 functions
in mucosal immunity (Parks et al.
2004
), the increased expression of MMP3 and
MMP10 may represent an altered host response and not compensation. Importantly,
most phenotypes reported in challenged MMP null mice are both qualitatively and
mechanistically distinct, and the fact that many different roles for specific MMPs
and TIMPs have been reported argues against compensation and redundancy within
the family
.
Furthermore, if one thinks about it, compensation is complex mecha-
nism. A cell would need to sense that it lacks some protein, then either upregulate or
induce de novo expression of another, related protein to carry out the missing task.
Redundancy is distinct from compensation and refers to different mechanisms
that carry out the same biological process. An example of redundancy is the many
ways in which an epithelium can ward off invading pathogens: exfoliation, muco-
ciliary clearance, production of a variety of antimicrobial factors (a significant
