Biology Reference
In-Depth Information
in the serum and urine, providing a useful markers for bone resorption (Atley et al.
2000
). Cathepsin K has also been shown to be capable of cleaving SPARC/
osteonectin, a glycoprotein involved in calcium binding (Bossard et al.
1996
).
Potential functions of this cleavage will be discussed below.
The cleavage of type I collagen by cathepsin K may also create bioactive peptides.
Type I collagen contains seven cryptic RGD sequences known to be important for
cell attachment. The ability of an osteoclast to form the resorption lacuna depends on
its ability to form actin rings, which requires an interaction between
3integrin
receptors and RGD epitopes in the matrix. In vitro experiments revealed that wild-
type osteoclasts plated on type I collagen could create actin rings; however, cathepsin
K-deficient osteoclasts were severely restricted in their ability to form actin rings
(Wilson et al.
2009b
), suggesting that the cryptic RGD sequences within type I
collagen require proteolytic exposure by cathepsin K before osteoclast
a
v
b
3integ-
rin-dependent attachment. The exposure of RGD motifs by the proteolytic activity of
cathepsin K must be an extracellular event. Further, digestion of type I collagen by
cathepsin K led to the generation of soluble peptides and resulted in the inhibition of
resorption when added to murine osteoclast cultures in a manner similar to synthetic
RGD peptides (Wilson et al.
2009b
). The in vivo generation of small RGD peptides is
likely an extra- as well as intracellular event. RGD sequences have been shown to be
important for wound repair response and malignant tumor growth, suggesting a
potential role for cathepsin K in the release of these potent cell signals in different
systems. Figure
2.5
summarizes the effect of cathepsin K on the activation of
osteoclasts via RGD peptide processing.
Type II collagen is a major component of articular cartilage and is the main
protease target for conditions such as arthritis. As with type I collagen, collageno-
lytic MMPs have been shown to cleave type II collagen at a specific site in the
C-terminus resulting in the release of 1/4 and 3/4 fragments (Miller et al.
1976
).
Cathepsin K has been shown to be capable of cleaving type II collagen within the
helical region of the N-terminus, a unique capacity for this protease in collagen
digestion (Kafienah et al.
1998
).
Cathepsins K, S, and L are also capable of cleaving cartilage-residing proteo-
glycans such as aggrecan and link protein (Hou et al.
2003
). This cleavage aids in
the destabilization of cartilage and also releases glycosaminoglycans, which, as
previously mentioned, complex with cathepsin K enabling the degradation of colla-
gen (Hou et al.
2003
). Cathepsin K is now thought to play a major role in the
degradation of cartilage in osteoarthritis as its expression is increased in chondrocytes
of patients with osteoarthritis and has also been located to osteoclasts, synovial
fibroblasts, and macrophages in osteoarthritis and rheumatoid arthritis (Dejica et al.
2008
; Gravallese
2002
; Hou et al.
2002
,
2001
; Konttinen et al.
2002
; Vinardell et al.
2008
). Lower pH in the extracellular space of osteoarthritic patients suggests that
cathepsins are the main target proteases over other collagenases (Konttinen et al.
2002
). The inhibition of cathepsin K has been suggested as a potential therapeutic
target for arthritis (Svelander et al.
2009
). Cathepsins B and L expressed by chon-
drocytes are also thought to be involved in cartilage destabilization in arthritis
(Maciewicz and Wotton
1991
).
a
v
b
