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Fig. 8.8 Demineralized area
(DA) of bone matrix adjacent
to an osteoclast in bone from
a cathepsin K-deficient
mouse. Section stained with
the trichrome Goldner's stain.
The
green areas
denote bone
and the
orange
stained area is
demineralized bone
BONE
osteoclast
DA
expression of the enzyme resulted in a decreased resorption of bone (Xia et al.
1999
; Gowen
1997
; Ishikawa et al.
2001
; Stroup et al.
2001
). All data together
clearly show the important role played by cathepsin K in osteoclast-mediated
resorption of bone.
Not all parts of the skeleton, however, proved to be similarly affected when
cathepsin K was inactive. The long bones showed a more severe osteopetrotic
phenotype than the bones of the skull (Gowen et al.
1999
). A plausible explanation
for this difference in response is the finding that calvaria osteoclasts express a lower
level of cathepsin K activity and use next to this enzyme other enzymes to digest the
matrix of bone (Everts et al.
1999a
), see below.
Recently it was shown that also other cysteine proteinases participate in bone
resorption by osteoclasts (Everts et al.
2006
). By using mice deficient for cathepsin
B and/or cathepsin L, involvement of cathepsin B could not be shown but cathepsin
L appeared to play a role in the degradation by modulating the activity of matrix
metalloproteinases (MMPs). The use of a panel of enzyme inhibitors that were
selective for different cysteine proteinases demonstrated that in addition to cathep-
sin K yet unknown cysteine proteinases are involved in osteoclast-mediated bone
matrix degradation (Everts et al.
2006
).
8.2.6.2 Matrix Metalloproteinases and Bone Matrix Degradation
In a series of studies by Delaisse et al. (
1985
), next to the participation of cysteine
proteinases also the role of MMPs was investigated. They showed that MMPs were
indeed somehow involved in the sequence of events that results in bone degrada-
tion. It was not clear, however, what their exact role was and which member of this
class of enzymes participates in the different steps of the resorption process.
By using isolated osteoclasts or osteoclasts that were generated in vitro, in
various studies it was shown that the actual resorption was not affected when
MMP-activity was blocked (Holliday et al.
1997
; Delaisse et al.
1987
; Fuller and
Chambers
1995
). These findings strongly suggested that osteoclast-mediated
resorption did not involve the activity of MMPs. Yet, some data appear to suggest
differently. The osteoclasts used for the analyses mentioned above were isolated
