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in apoptosis), regulation of blood coagulation and the complement system, the
processing of precursor proteins (e.g., proenzymes, prohormones, and antigen
processing), and the physiological or pathological degradation of the extracellular
matrix (ECM) (see reviews Brix et al. 2008 ; Turk et al. 2001 ; Vasiljeva et al. 2007 ).
ECM degradation can be catalyzed by membrane-bound and secreted proteases.
Historically, matrix metalloproteases (MMPs) have been considered as the main
actors of ECM degradation (Brinckerhoff and Matrisian 2002 ; Burrage et al. 2006 ;
Parsons et al. 1997 ; Shapiro 1994 ). This was justified by their cell membrane
association or extracellular localization, their neutral pH activity optima, and
their ability to degrade structural extracellular proteins such as collagens, elastin,
and proteoglycans. Furthermore, their association with various diseases where
ECM degradation is a prominent feature such as arthritic joint erosion, atheroscle-
rotic plaque formation, tumor invasion and metastasis has supported the notion that
MMPs are pivotal under pathological conditions and thus represent excellent
targets for therapeutic interventions.
However, various studies seemed to contradict the central and critical role of
MMPs in ECM degradation. For example, stromelysin (MMP3)-deficient mice
exhibited an increased arthritic phenotype (Mudgett et al. 1998 ). MMP inhibitors
in cancer treatment trials failed dramatically despite the prominent role given to
these proteases in the progression of tumor growth and metastasis (Turk 2006 ;
Zucker et al. 2000 ). These unexpected results might have been caused by selecting
the wrong matrix metalloprotease targets or by the insufficient specificities of the
inhibitors used. These results may also indicate that the main function of MMPs lies
outside of bulk matrix degradation and more in the highly regulated processing of
extracellular proteins. The laboratory of Overall has pioneered MMP substrate
identification methods, which revealed a multitude of nonmatrix proteins as
MMP targets (Butler and Overall 2009 ; Morrison et al. 2009 ). This included the
activation and inactivation of various growth factors and other “signaling” proteins,
which clearly indicated that MMPs might have a critical regulatory role in ECM
metabolism (McQuibban et al. 2000 ; Overall and Blobel 2007 ). Moreover, the
cleavage specificities of classical matrix metalloproteases such as collagenases and
aggrecanases are highly specific and cleave their target substrates only at single or a
very limited number of peptide bonds. For example, MMP collagenases cleave
specifically a single peptide bond in type I and II collagens and generate typical 1/4
and 3/4 fragments. Aggrecanases hydrolyze specifically one or two peptide bonds
between the G1 and G2 interdomain of the major cartilage resident proteoglycan
(Tortorella et al. 2000 ; Westling et al. 2002 ). On the other hand, ECM-degrading
pathologies such as osteoporosis and arthritis suggested a more aggressive and
nonspecific proteolytic action. The involvement of proteases other than MMPs in
matrix degradation was indicated early on in experiments using cysteine protease
inhibitors. For example, it was shown that E64, a pan cysteine cathepsin inhibitor,
strongly inhibited osteoclast-mediated bone resorption (Everts et al. 1988 ). Similarly,
cysteine protease inhibitors proved highly potent in proteoglycan degradation experi-
ments (Buttle et al. 1992 , 1993 ) and tumor/metastasis related assays (Jedeszko and
Sloane 2004 ). Various cathepsin knockout mice models revealed decreased disease
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