Biology Reference
In-Depth Information
8.2.6 Release of Enzymes Results in Digestion
of the Bone Matrix
Next to the dissolution of the mineral of bone, the second major constituent, the
matrix, has to be digested. The matrix of bone contains a variety of proteins, of
which collagen type I is the one far out the most abundantly present. Some proteins
that are relatively bone specific are bone sialoprotein, osteocalcin and osteopontin.
These proteins play an essential role in the modulation of mineral crystal formation
(Jahnen-Dechent et al.
2008
). Finally, the matrix contains a relatively low level of
proteoglycans. All these components are digested in the ruffled border area by a
variety of enzymes of which the proteolytic enzymes are probably the most
important ones.
The proteolytic enzymes which have been shown to be functional in the process
resulting in the degradation of the matrix are members of the cysteine proteinases,
the matrix metalloproteinases and the serine proteinases (Delaisse et al.
2000
). Next
to enzymes essential for protein degradation, a high level of TRACP is secreted in
the ruffled border area. The role of these different enzymes will be discussed in the
following paragraphs.
8.2.6.1 Cysteine Proteinases, in Particular Cathepsin K, and Their Role
in Bone Degradation
Delaisse et al. (
1984
) were the first to demonstrate the involvement of cysteine
proteinases in osteoclast-mediated degradation of bone. These authors used selec-
tive inhibitors of this class of enzymes and demonstrated both in vivo and in vitro
that blockage of the activity of cysteine proteinases resulted in a decreased degra-
dation of bone.
What occurs at the cellular level in the absence of cysteine proteinase activity
was found initially in bone biopsies obtained from patients suffering from the rare
osteopetrosis-like disease pycnodysostosis. Adjacent to the osteoclasts of these
patients a high amount of non-digested bone matrix was found ((Everts et al.
1985
), Fig.
8.6
). Demineralization proved to continue but the cells did not have
the capacity to digest the matrix. This observation suggested that enzymes involved
in matrix degradation were not expressed or not active. Subsequently by using
selective inhibitors of cysteine proteinases in an in vitro bone explant system, it was
shown that similar non-digested but demineralized areas were present next to
actively resorbing osteoclasts (Fig.
8.7
, (Everts et al.
1988
)). Collectively these
findings provided proof for the participation of cysteine proteinases in osteoclast-
mediated bone matrix resorption.
In the mean time some groups detected that osteoclasts express a relatively
unique member of the group of cysteine proteinases, cathepsin K, an enzyme that
proved indeed to be essential for bone resorption by osteoclasts (Bromme et al.
1996
; Xia et al.
1999
). Mice deficient for this enzyme were characterized by a mild
