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In-Depth Information
High salt concentrations, which interfere with the ionic binding between the neg-
atively charged glycosaminoglycans and the positively charged cathepsin K bind-
ing site, also inhibit the collagenase activity of cathepsin K (Li et al.
2002
). The
formation of cathepsin/glycosaminoglycan complexes is mostly specific for cathep-
sin K. The only exception is cathepsin V which also forms weak complexes with
glycosaminoglycans but lacks a collagenase activity (Bromme et al.
1999
; Yasuda
et al.
2004
). This indicates that the formation of the protease/glycosaminoglycan
complex is not the only prerequisite for the potent collagenase activity of cathepsin K.
Highly repetitive motifs in triple helical collagens are Gly-Pro-X and Gly-X-
Hyp with X and Y representing various amino acids. About 17% of all amino acid
residues are proline or hydroxyproline. Identified cathepsin K cleavage sites within
the type I and II collagens revealed the acceptance of proline residues in the S1 and
S2 subsites of the substrate binding area of the protease (Garnero et al.
1998
;
Kafienah et al.
1998
). This is a unique feature for cathepsin K as other cathepsins
exclude proline from these subsites (Choe et al.
2006
). Consequently, the mutation
of the S2 subsite into a cathepsin L-like one which excludes the binding of proline
significantly reduced the collagenase activity of the cathepsin K variant (Lecaille
et al.
2002a
). This may explain the lack of a collagenase activity of cathepsin V
despite its ability to form a complex with chondroitin sulfate. Cathepsin V does not
accept proline in the P2 position of substrates (Choe et al.
2006
).
2.5 Role of Cathepsins in Extracellular Matrix Degradation
2.5.1 Bone and Cartilage (Collagenolytic and Proteoglycan-
Degrading Cathepsins)
Bone and cartilage contain specialized ECM components, which give strength
and structural qualities. Bone organic matrix contains predominantly type I colla-
gen (90%). The rest of the bone is composed of inorganic mineral components such
as hydroxyapatite and noncollagenous proteins such as osteopontin, osteocalcin,
osteonectin, fibronectin, thrombospondin, and bone sialoprotein.
During bone resorption, the degradation of type I collagen is essential; many
enzymes such as MMP collagenases are present but the majority of the degrada-
tion is performed by cathepsin K. Cathepsin K was originally cloned from rabbit
osteoclasts where it was suggested to have a role in bone remodeling and bone
diseases (Tezuka et al.
1994
). Specialized bone resorbing cells named osteoclasts
have since been shown to express a high level of cathepsin K (Bromme and
Okamoto
1995
; Drake et al.
1996
; Kamiya et al.
1998
; Littlewood-Evans et al.
1997
). Osteoclasts are able to acidify an isolated area between the cell and bone
matrix named the resorption lacuna (Silver et al.
1988
). This results in the dissolu-
tion of the mineral component releasing the matrix collagen and provides an acidic
environment for secreted cathepsin K (see also Chap. 8). Cathepsin K was found to
