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In-Depth Information
intracellular banded collagen could indeed be demonstrated, reflecting a preceding
phagocytic uptake event (Curino et al.
2005
).
3.4 Collaboration Between Pericellular and Endocytic
Collagen Degradation Pathways
That the extracellular MMP collagenase/cathepsin K systems and the endocytic
collagen degradation pathways that have been described in the preceding sections
would act in concert to organize the complete degradation of collagen appears
intuitively obvious. Mature collagen structures are orders of magnitudes larger than
individual cells and, thus, the cellular internalization of collagen by either mannose
receptor family members or collagen-binding integrins would be predicated on
initial cleavage of collagen by pericellular/extracellular collagenases to generate
collagen fragments of a manageable size for the cellular endocytosis apparatus.
Conversely, MMP collagenases or cathepsin K is incapable of completely degrad-
ing collagen, but rather facilitates the formation of partially degraded collagen
fragments that are released into the interstitium or the circulation, where they would
become targets for endocytic uptake by cells. This notion of a tight integration of
extracellular and intracellular collagen degradation pathways is further supported
by in vivo localization studies revealing that cells that are actively engaged in
collagen turnover express both collagenases and collagen endocytic receptors
during physiological as well as malignant tissue remodeling (Curino et al.
2005
;
Schnack Nielsen et al.
2002
; Wagenaar-Miller et al.
2007
), and by the burgeoning
functional studies described below.
3.4.1 Collagenases and uPARAP/Endo180-Mediated Collagen
Endocytosis
As both uPARAP/Endo180 and MMP-14 have important functions in collagen
turnover in connection with bone growth, a genetic study was performed to reveal
the mutual dependence of their associated functions. A littermate-controlled pro-
gram was set up to compare wild-type mice and mice that were homozygously
deficient for either uPARAP/Endo180 or MMP-14, or homozygously double defi-
cient (Wagenaar-Miller et al.
2007
). Even compared with the clearly compromised
MMP-14-deficient mice, the double-deficient mice turned out to display a strongly
worsened phenotype. They had a lifespan of less than 3 weeks and very severe
skeletal defects, including a lack of cranial closure and delayed bone growth. Since
all phenotypic consequences were compatible with defects in bone collagen remo-
deling, it appears that the turnover mechanisms supported by uPARAP/Endo180
and MMP-14, respectively, can to some extent complement each other. On the
