Biomedical Engineering Reference
In-Depth Information
2.2.1.2 Inflammatory Bowel Disease (IBD)
IBD is a chronicle inflammatory condition of the intestine, mostly leading to
vomiting, diarrhoea, and rectal bleeding.
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Crohn's disease (CD) and ulcerative
colitis (UC) are the main forms of IBD, differing in localization and histology
of the inflammatory changes. UC is restricted to the epithelial mucosa of the
colon and the rectum, while CD can affect the whole bowel wall through the
entire gastrointestinal tract. To date, little is known about the development of
the disease, but the latest genetic approaches have identified several potentially
relevant genes.
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The human metalloproteases meprin a (MEP1A) is one of these candi-
dates.
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Banerjee and colleagues showed that MEP1A is genetically associated
with IBD, based on SNPs (single nucleotide polymorphisms) in UC patients
and a decreased mRNA expression in the epithelium. This is further sup-
ported by DSS- (dextran sodium sulfate) treated meprin a knockout mice,
which showed stronger inflammation and intestinal injury than the wild-type
animals and by mRNA expression in intestine-specific HNF4a (hepatocyte
nuclear factor 4a) null mice.
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In the DSS-induced colitis model, these
animals showed not only more severe changes in clinical symptoms and
pathologies associated with IBD, but also a decrease in meprin a and b
expression in epithelial cells.
However, the substrates for meprins are still ambiguous, and whether meprin
a is a suitable target for therapeutics remains unproven. Promising substrates
are interleukins (ILs) which are associated with IBD. Several reports deal with
the activation of IL-1b and IL-18 by meprin b, subsequently influencing
inflammatory processes.
40,49,50
However, these growth factors are not pro-
cessed by meprin a, but others are, such as vascular endothelial growth factor-
A (VEGF-A).
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2.2.2 Angiogenesis and Cancer
A Morpholino knockdown in zebrafish embryos targeting meprin b mRNA led
to a decreased amount of protein, which caused defects in general tissue dif-
ferentiation, subsequently leading to death before hatching.
41
This demon-
strates the importance of the enzyme for cell differentiation and proliferation,
even during embryogenesis.
In contrast, meprin a morphants were affected more specifically and showed
severe failure in the formation of the vascular system (Figure 2.5B). The blood
circulation was largely diminished, resulting in erythrocyte accumulation (Fig-
ure 2.5C), suggesting the hypothesis of a pro-angiogenic effect for meprin a.
These phenotypes mimic a previously described VEGF-A morphant, revealing a
possible role of meprin a in VEGF-A activation. Indeed, human recombinant
meprin a processed vascular endothelial growth factor-A (VEGF-A) specifi-
cally, revealing the same cleavage products detectable for VEGF from zebrafish.
Thus, meprin a plays a significant role in VEGF-A processing, subsequently
being involved in the regulation of angiogenesis.
