Biology Reference
In-Depth Information
respectively. Due to a high content of imino acids and repeated Gly in every third
residue, the
chain adopts a left-handed poly-Pro II-like helix and three left-handed
chains intertwine to form a right-handed superhelix (Ramachandran and Kartha
1955
; Rich and Crick
1961
; Kramer et al.
2001
). Such triple helical structures make
interstitial collagens resistant to most proteolytic enzymes. Only a limited number
of enzymes can degrade native interstitial collagens, and “collagenolysis” often
refers to degradation of types I, II and III collagens, as other types of collagens are
degraded by a broader spectrum of proteinases.
The first collagenolytic activity was discovered in the culture medium of
Clos-
tridium histolyticum
, a pathogenic anaerobic bacterium that causes gas gangrene
(Jennison
1947
; Mandl et al.
1953
). The enzyme is referred to as bacterial collage-
nase or
Clostridium
collagenase. The discovery of vertebrate collagenase had to
wait until 1962 when Gross and Lapiere reported collagenase activity in tadpole
tail skins, gut and gills undergoing metamorphosis (Gross and Lapiere
1962
). While
bacterial collagenase cleaves triple helical collagen I at multiple sites, the tadpole
enzyme cleaves long filamentous collagen I at a single site
a
away from the
¾
N-terminus and generates characteristic
and ¼ fragments (Nagai et al.
1966
).
This discovery encouraged many researchers to search for collagenase activity in
mammalian tissues as it was considered to be important not only in normal tissue
remodelling and repair, but also in diseases such as skin ulceration, arthritis, cancer,
atherosclerosis and periodontitis. Human collagenase was first purified from the
medium of rheumatoid synovium (Woolley et al.
1975
); this is now called collage-
nase 1 or MMP-1 as the first member of the matrix metalloproteinase (MMP)
family, which encompasses a large number of members including 23 MMPs in
man. However, MMPs that have collagenolytic triple helicase activity are limited.
Other mammalian collagenases are MMP-8 (collagenases 2 or neutrophil collage-
nase) and MMP-13 (collagenase 3). Xenopus has MMP-18 (collagenase 4), but its
counterpart has not been found in mammals. Rheumatoid synoviocytes in culture
also produce MMP-2 and MMP-3 (Okada et al.
1986
). MMP-2 (gelatinase A) was
originally characterized as a gelatinase (Murphy et al.
1985
; Okada et al.
1986
), but
in 1995 Aimes and Quigley reported its collagenolytic activity (Aimes and Quigley
1995
). Another major collagenolytic MMP is membrane-type-1 MMP (MT1-MMP
or MMP-14). It is a major pericellular collagenase, and mice lacking MMP-14
exhibit skeletal abnormalities due to the lack of tissue collagenolytic activity
(Holmbeck et al.
1999
). MMP-14 also activates the zymogen of MMP-2 (pro-
MMP-2) on the cell surface (Sato et al.
1994
). Thus, MMP-2 and MMP-14 exhibit
important pericellular collagenolytic activity. These MMPs are produced by
many cell types such as fibroblasts, epithelial cells, macrophages, leukocytes,
endothelial cells, smooth muscle cells, chondrocytes and osteoblasts, and they
have been characterized to have the ability to cleave collagen I similar to tadpole
collagenases, at neutral pH.
For bone to be remodelled, the non-mineralized collagen I matrix must be
cleaved, and the lysosomal cysteine proteinase, cathepsin K, is considered to be
the major collagenolytic enzyme (Gelb et al.
1996
; Hou et al.
1999
). It is mainly
produced in osteoclasts (Br
¾
omme et al.
1996
), but also in other cell types such as
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