84 Etiopathogenesis of Cruciate Ligament Rupture
distribution of apoptotic cells in different
segments of partially torn CrCLs suggests that
apoptosis in ligament fibroblasts is present
before mechanical disruption of the ligament
(Krayeret al. 2008).
Recent evidence has shown that ROS
may have an opposing activity in cytokine-
stimulated chondrocytes, suggesting that the
role of NO in OA may be more complex than
originally believed. Chondrocytes respond to
NO or ROS differently depending on the inten-
sity, duration of the signaling, and the cellular
redox status. For example, in a zymosan-
induced arthritis model, NO and peroxynitrite
induced inflammation and proteoglycan loss.
While the addition of a selective iNOS inhibitor
ameliorated only synovial inflammation, uric
acid (a peroxynitrite scavenger) was able to
decrease inflammation and proteoglycan loss,
suggesting that targeting peroxynitrite might
be more effective for protection against OA
(Bezerraet al. 2004).
It has also been shown that NO mediates the
expression of pro-inflammatory cytokines such
as IL-18 and IL-1 converting enzyme (Boileau
et al. 2002). Pro-inflammatory mediators such as
NO, IL-1, TNF, and prostaglandins are all over-
produced in chondrocytes from patients with
OA (Weinberget al. 2007).
MMP: An overview
The matrix metalloproteinases (MMPs) are a
group of structurally and functionally related
enzymes responsible for the proteolytic degra-
dation of ECM and basal membrane com-
ponents. Broad functions in defense, injury,
inflammation and normal tissue remodeling
have been attributed to MMPs (Manicone &
McGuire 2008). The role of MMPs in matrix
degradation and remodeling is considered to
be most important in the context of cruciate
ligament rupture (CR) and stifle arthritis. Due
to their potential detrimental effects, MMPs
are highly regulated at different levels. At the
level of transcription, MMP expression is con-
trolled by multiple cytokines and growth fac-
tors. Moreover, MMPs are secreted as inactive
proMMPs (also called latent MMP or zymogen),
which then require activation that is initiated
by plasmin or membrane-type MMP. A third
level of regulation includes the local produc-
tion of specific tissue inhibitors of metallopro-
teinases (TIMPs) (Ries & Petrides 1995; Nagase
et al. 2006). TIMP concentrations generally far
exceed the concentrations of MMPs in tissue,
thereby limiting their proteolytic activity in the
pericellular environment.
MMPs in the articular environment are
produced by synovial cells, osteoblasts, chon-
drocytes and ligament fibroblasts, as well as by
monocyte/macrophages or neutrophils. MMPs
capable of degrading the macromolecules of the
ECM comprise three subclasses with respect
to their substrate specificity: collagenases,
gelatinases, and stromelysins. The collagenases
(MMP-1, -8, and 13) are responsible for the first
degradation step of collagen by cleaving the
interstitial collagens I, II, and III. Collagen II
is the main collagen type of hyaline cartilage,
while collagen I forms the principal tensile-
resistant fiber of ligaments. The denatured
collagen, or gelatin, is further degraded by the
gelatinases (MMP-2, and -9). Among these,
MMP-13 has been frequently reported to be
the most important player in OA cartilage due
to its ability to degrade collagens more effec-
tively (Murphy & Nagase 2008). Stromelysins
(MMP-3, -10, and 11) have a broader specificity,
including collagen type III, IV, V, VII, IX, XI,
as well as proteoglycans, gelatin, laminin
and fibronectin, and can also activate other
MMPs. MMP-2 and MMP-9 also cleave gelatin,
fibronectin and elastin beside collagen type IV
and V (Manicone & McGuire 2008).
Although details in signaling and control
mechanisms involved in MMP regulation
remain to be elucidated, recent findings have
been useful in developing an understanding of
the complex regulation of MMP synthesis and
activity.The role of MMPs in the stifle joint
MMPs play a key role in the progression of var-
ious joint diseases and influence joint inflam-
mation and matrix degradation. Most actions
of MMPs in joints are catabolic in nature (Fig-
ure 10.2). They are associated with increased
ECM degeneration of cartilage or ligaments,
and serve as significant cofactors in inflam-
matory reactions (Fooset al. 2001; Muiret al.