Biology Reference
In-Depth Information
the extremely tight attachment of the osteoclast to the bone, which allows for the
subsequent formation of an osteoclast lacuna or resorption pit at the bone-osteoclast
interface, wherein an acidic microenvironment (pH 4.5) can be generated by the
active secretion of H
+
ions by vacuolar-type ATPases and by the passive transport of
Cl
ions through chloride channels (Roodman
2006
). Unlike MMP collagenases,
cathepsin K is active at a low pH, cleaves the acid-exposed collagen at multiple sites
within the triple helix, and also degrades the nonhelical N- and C-telopeptide regions
(Bossard et al.
1996
; Garnero et al.
1998
; Kafienah et al.
1998
). The cleavage sites for
cathepsin K do not overlap the MMP collagenase cleavage site. The partially
degraded collagenaceous material that is generated by cathepsin K is then released
from the osteoclast into the extracellular environment by the process of transcytosis
(Nesbitt and Horton
1997
;Saloetal.
1997
), and it is further degraded by cellular
uptake and lysosomal degradation via specific endocytic collagen degradation path-
ways (see Sect.
3.4
).
The above model for cathepsin K-mediated collagen degradation during bone
resorption is supported by studies of cathepsin K deficiency in humans (pycnody-
sostosis) (Gelb et al.
1996
). Cathepsin K-deficient individuals have greatly dimin-
ished capacity to remodel bone, which leads to osteopetrosis, tooth retention, failure
to close cranial sutures, and short and brittle bones (Helfrich
2003
). Osteoclasts
from pycnodysostosis patients also display a distinct accumulation of collagenac-
eous material within the resorption lacunas as well as in intracellular vesicles
engaged in collagen transcytosis, and the release of collagen fragments to the
blood stream is greatly diminished (Everts et al.
1985
). The above findings from
studies of human patients are largely replicated in cathepsin K-deficient mice
(Gowen et al.
1999
; Saftig et al.
1998
). Interestingly, whereas the concentration
of cathepsin-generated collagen fragments in the blood stream is low in cathepsin
K-deficient individuals, the concentration of MMP collagenase-generated collagen
degradation products is increased, suggesting a partial functional overlap between
the two principal pathways for extracellular collagen turnover (Nishi et al.
1999
).
See Chap. 2 of this volume for a review of cathepsin proteases.
3.2.3 Extracellular Collagen Degradation in Cancer
In the transition from local to metastatic disease, carcinoma cells must transverse the
basement membrane underlying the site of origin, as well as the subadjacent intersti-
tial matrix. Both are rich in crosslinked collagens that form a physical barrier that
must be proteolytically degraded for transversion by tumor cells. Indeed, it was an
early realization that tumor dissemination was a proteolysis-dependent process and
that it might be controlled by the inhibition of the proteases responsible for basement
and interstitial matrix degradation, which has spurred an intense effort over the last
four decades to identify these enzymes [reviewed in Dano et al. (
1985
)andLiotta
et al. (
1982
)]. These studies have revealed that scores of soluble and membrane-
associated proteolytic enzymes are abnormally expressed in either tumor cells or
