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other hand, as MMP-14 acts in partial redundancy with MMP-16 to degrade
collagen during osteogenesis (Shi et al.
2008
), the very severe phenotype of
uPARAP/Endo180 and MMP-14 double-deficient mice could, alternatively, be a
consequence of the combined impairment of sequential and interdependent peri-
cellular and endocytic collagen degradation pathways. Indeed, studies with isolated
cells have indicated a functional association between MMP-14 and uPARAP/
Endo180. When grown on a reconstituted type-I collagen matrix, wild-type fibro-
blasts successfully degraded this matrix whereas MMP-14-deficient cells failed to
do so. Fibroblasts deficient for uPARAP/Endo180 did degrade the matrix, but in
these cultures defined collagen fragments accumulated in the culture medium
(Madsen et al.
2007
). Since the accumulated collagen was efficiently cleared by
wild-type cells, these data point to a sequential reaction where the first collagen
cleavage step is performed by MMP-14, after which the initial cleavage products
are endocytosed by uPARAP/Endo180 for intracellular degradation. This is in line
with the high uptake efficiency of uPARAP/Endo180 for defined collagen frag-
ments mentioned above.
3.4.2 Clearance of Circulating Bone-Derived Gelatin
by the Mannose Receptor
The remodeling of bone by osteoclasts in a normal individual is estimated to lead to
the release of more than half a gram of partially degraded collagen into the
bloodstream per day (see Sect.
3.2.2
and Chap. 2 in this volume), and this material
is efficiently cleared by hepatic sinusoidal endothelial cells. The MR appears to be a
dominant endocytic receptor in the uptake of collagen/denatured collagen frag-
ments from the blood. Thus, when labeled denatured collagen was injected intrave-
nously into MR-deficient mice, these mice displayed a greatly delayed clearance of
this material, as compared to wild-type mice, and MR deficient sinusoidal endothe-
lial cells were unable to internalize the same material when explanted in culture
(Malovic et al.
2007
). A probably unrelated endocytic activity of the MR is directed
to the C-terminal procollagen propeptides, liberated by MMPs or cathepsin K
cleavage during collagen turnover, which, most likely, bind through the lectin
function of the MR. Strikingly, these prodomains accumulate specifically in the
blood of MR-deficient mice (Lee et al.
2002
; Sturge et al.
2007
).
3.4.3 MT-MMP and Integrin Cooperativity in Collagen
Internalization
As evident from the discussion above, cooperative actions between MMPs and
receptors of the mannose receptor family can lead to collagen cleavage into defined
