Biology Reference
In-Depth Information
such as MMP-2, MMP-3, MMP-13, cathepsin B, cathepsin L, neutrophil elastase
and cathepsin G may be important components for fibrillar collagen hydrolysis.
Such action would also remove crosslinking sites from the fibrils (Wu et al.
1991
).
Alternatively thinner fibrils or mechanically damaged collagen fibrils may expose
the collagenase cleavage sites and initiate collagenolysis.
Saffarian et al. (
2004
) reported that active MMP-1 moves in one direction on
reconstituted collagen fibrils, like a molecular ratchet which is driven by proteoly-
sis. This movement may be explained from the Orgel model of collagen fibrils:
Upon removal of the C-telopetide or damaging of a part of fibrils, collagenase can
cleave and remove the C-terminal ¼ fragment, including the C-telopeptide of the
collagen molecule, which then reveals the C-terminally adjacent collagenase
cleavage site. Subsequent cleavage of this site will expose another cleavage site
on the C-terminal of the previous cleavage site, as illustrated in Fig.
5.7
. Such
directional movement of collagenase may be associated with directional cell
movement in the tissue when the cells express MMP-14 or soluble collagenase
attaches to the cell surface. For example, MMP-1 binds to
1 integrin (Stricker
et al.
2001
) and to Emmprin (CD147/Basigin) (Guo et al.
2000
). The pericellular
cleavage of collagen fibrils by MT1-MMP appears to give directional cell move-
ment on collagen fibrils (Wolf et al.
2007
). Cells such as inflammatory cells and
keratinocytes may use such mechanisms and move along in one direction depend-
ing on the orientation of collagen fibrils. According to Orgel's model, the
a
2
b
1
integrin binding site located in the D3 is also blocked by the adjacent collagen
molecule (Sweeney et al.
2008
). To make these sites available to the integrins,
collagenolysis and denaturation of the
a
2
b
fragment may be necessary. Further
investigation is necessary to ascertain how the cell moves along the collagen
fibrils and its association of pericellular collagenolysis. In addition, the small
¾
Telopeptidase
1
2
3
4
5
6
Fig. 5.7 Directed collagenolysis of collagen fibrils. The Orgel model of rat tail tendon
collagen fibrils indicates that collagenase-cleavage sites in collagen fibrils are largely blocked
by C-telopeptides, suggesting that either telopeptidases need to cleave the C-telopeptide or the
structure needs to be distorted or damaged. This will initiate collagenase cleavage of the
collagen fibrils and remove the C-terminal ¼ fragments, which causes the subsequent cleavage
site located to the C-terminal to become exposed to collagenase. Thus, a single collagenase
molecule moves towards the C-terminal direction driven by proteolysis. The Orgel model
hence explains the ratchet movement of collagenase reported by Saffarian et al. (
2004
)
