Biomedical Engineering Reference
In-Depth Information
Additionally, meprin a expression differs between different carcinomas, with
quite low levels in ovarian cancer compared to gastrointestinal carcinomas. 84
Hence, the role of meprins in cancer development, progression, and metastasis
seems to be more complex than the ECM-degrading function known for certain
MMPs. Here, the processing of growth factors and cytokines, especially with
regard to the pro-angiogenic function of meprin a, should be given emphasis in
future studies.
Overall, meprin a might be a new therapeutic target in cardiovascular dis-
eases and/or tumor growth inhibition. The latter requires highly specific and
potent reagents to inhibit the proteolytic activity of meprin a. Again, the
hydroxamate actinonin could be a template, owing to its K i for this protease in
the nanomolar range.
In contrast, to benefit the positive effect of meprin a, the enhancement of
vascularization under physiological conditions is more dicult to achieve.
Here, it would be necessary to apply the enzyme directly to the affected tissue.
2.2.3 Fibrosis
Fibrosis is characterized by the excess of fibrous connective tissue in an organ
or tissue as a reparative or reactive process. Scarring of a wound is a physio-
logical condition, normally harmless and protective against infections, but
some related diseases, e.g. cirrhosis, pulmonary fibrosis, and myelofibrosis,
have dramatic consequences for the patient health, which can even lead to
death. Although many different factors may be the cause for these pathologic
conditions, the strong increase in the formation of fibrillar collagen is one of the
crucial molecular processes.
For many years, three groups of proteinases have been exclusively implicated
in the maturation of the fibrillar procollagens (I, II, III, V, and I2). The tolloid
proteinases (including BMP-1) perform C-terminal processing, while
ADAMTS-2, 3, and 14 cleave off the N-terminal propeptides. The furin-like
proprotein convertases, as well as tolloid proteinases, are also involved in N-
and C-terminal processing of the minor fibrillar collagens (V and 2I). 14,85
Recently, it has been shown that meprins are also capable of cleaving pro-
collagens (Figure 2.6). 48 Meprin a and b both release the N- and C-propeptides
from procollagen III, a critical step in collagen fibril formation. In addition,
both meprins cleave procollagen III at exactly the same site as the procollagen
C-proteinase BMP-1. Indeed, cleavage of procollagen III by meprins is more
ecient than by BMP-1. To determine the physiological consequences, normal
and fibrotic (keloid) skin was analyzed regarding the expression of human
meprins. Interestingly, in contrast to healthy skin, where meprins are pre-
dominantly expressed in keratinocytes of the epidermis (Figure 2.6A), an
enhanced expression of both meprin a and b was observed in dermal fibroblast
of keloid tissues (Figure 2.6B). 39 These cells are the main source for fibrillar
collagens, revealing a link between fibrosis and the proteolytic activity of
meprins. This is supported by the demonstration that meprin a affects
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