Biology Reference
In-Depth Information
turnover during both the development and the maintenance of connective tissues
(Holmbeck et al.
2004
; Krane and Inada
2008
). This was first evidenced by the
severe defects in the development and maintenance of bone, cartilage, and connec-
tive tissues of MMP-14-deficient mice, and by the associated failure of mesenchy-
mal cells residing in the tissues of these mice to degrade fibrillar collagen in vitro
(Holmbeck et al.
1999
; Zhou et al.
2000
). MMP-14 function in part may overlap that
of MMP-16, as mice deficient in the latter collagenase display the similar spectrum
of defects, though milder, which are greatly exacerbated by the combined absence of
bothMMP collagenases (Shi et al.
2008
). Analysis of mice with null mutations in the
soluble MMP collagenases has also affirmed their role in physiological collagen
turnover, with the possible exception of MMP-8 (Balbin et al.
2003
). Thus, mice
with single deficiencies in MMP-2 and MMP-13 display skeletal defects that likely
can be directly attributed to impaired collagen turnover (Inada et al.
2004
; Inoue
et al.
2006
; Mosig et al.
2007
; Stickens et al.
2004
). Cell-based assays of fibrillar
collagen degradation have also lent support to the notion of membrane-bound
collagenases as the principal mediators of the initial stages of collagen turnover.
A series of elegant loss of function and gain of function studies have revealed that
only deficiency in membrane-bound MMP collagenases can abrogate the collagen
degrading and collagen invasive activity of a variety of cultured mesenchymal cells,
and, conversely, only gene transfer of membrane-bound MMP collagenases can
confer collagen degrading capacity to cells that are normally unable to do so (Chun
et al.
2004
; Hotary et al.
2000
,
2003
,
2006
; Sabeh et al.
2004
; Shi et al.
2008
;
Wagenaar-Miller et al.
2007
). One exception to this pattern is cultured human and
mouse keratinocytes, whose collagen degrading capacity is independent of mem-
brane-bound MMP collagenases, but appears to be strictly dependent on, respec-
tively, MMP-1 and MMP-13 (Netzel-Arnett et al.
2002
; Pilcher et al.
1997
).
3.2.2 The Cathepsin K System
Vertebrate bone is among the tissues with the highest content of collagen, which
constitutes about 90% of the total protein, mainly in the form of type-I collagen fibers
that form a tight network enmeshed in the bone mineral matrix (Linsenmayer
1991
;
van der Rest and Garrone
1991
). Bone is characterized by a relatively high rate of
turnover, even under homeostatic conditions, with new bone being continuously laid
down by osteoblasts and subsequently resorbed by osteoclasts (Zaidi et al.
2003
).
This osteoclast-dependent collagen breakdown is mediated not primarily by MMP
collagenases, but rather by members of the cysteine proteinase family of lysosomal
cathepsins, in particular the enzyme cathepsin K (Lecaille et al.
2008
; Segovia-
Silvestre et al.
2009
). Cathepsin K is a typical cysteine cathepsin with a catalytic
Cys, His, Asn triad located in the active site. The protease is synthesized as a 37-kDa
glycosylated proenzyme (zymogen) that is activated by proteolytic removal of the
propeptide induced by low pH (Lecaille et al.
2008
). Osteoclast-dependent
collagenolysis is a complex, yet fairly well understood, process that is initiated by
