Advances in the Canine Cranial Cruciate Ligament, 2nd edition

68 Etiopathogenesis of Cruciate Ligament Rupture

neoepitope (or ARGS-aggrecan), a breakdown
product of cartilage, have been found to be ele-
vated in human synovial fluid after acute ACL
injury. An increase in TIMP-3 at six months
after the injury was reported, suggesting an
inhibitory effect on further cartilage degrada-
tion (Tourvilleet al. 2015). However, little atten-
tion has been centered on the presence and
expression of these proteases in the normal
canine CrCL.
The role that the CrCL plays in the mechan-
ical integrity of the canine stifle joint has been
well described (Stoufferet al. 1983; Vasseur
1993; Wingfieldet al. 2000). Excessive motion
of the canine stifle joint is prevented by liga-
mentous constraints (the CrCL primarily resist-
ing cranial tibial displacement) and a complex
system of reflex arcs from surrounding mus-
cle groups (Vasseur & Arnoczky 1981; Vasseur
1993). Although the joint capsule has also been
shown to contribute significantly to cranio-
caudal stability in the canine stifle, the role of
the CrCL surpasses this contribution (Lopez
et al. 2003).

Metabolism in ruptured canine cruciate
ligaments

ECM metabolism in ruptured canine CrCLs
has been investigated (Muiret al. 2002; Comer-
fordet al. 2004). In one study (Comerfordet al.
2004), CrCLs from normal Labrador Retrievers,
a breed at high-risk of CR, and from Labrador
Retrievers with CR were examined. Ruptured
CrCLs had significantly higher amounts of
immature crosslinks, total and sulfated gly-
cosoaminoglycans (GAGs), and water content,
compared with that of the intact ligaments.
Compared with intact CrCLs, the concentra-
tion of pro-MMP-2 (inactive MMP-2) was sig-
nificantly higher, and the maximum tempera-
ture of collagen denaturation was significantly
lower in the ruptured CrCLs (Figures 8.2 and
8.3) (Comerfordet al. 2004). These studies sug-
gested that the ECM of ruptured CrCLs had
an increased matrix turnover, as indicated by a
higher collagen and GAG synthesis, compared
with that of intact CrCLs. It is likely that the
ECM changes may have occurred before liga-
ment rupture. However, it is possible that these
observed changes may form part of a reparative

300

200

100

0

Ruptured CrCLs Intact CrCLs

Percentage of MMP-2 standard

p = 0.02

Figure 8.2 Dot diagram of the pro-form of matrix

metalloproteinase 2 (pro-MMP-2) as a percentage of the

MMP-2 standard indicative of collagen remodeling in

seven ruptured and 11 intact cranial cruciate ligaments

(CrCLs) from 18 dogs. Horizontal lines represent the

mean values of each data set. Source: Comerfordet al.

2004. Reproduced with permission from the American
      Veterinary Medical Association.

process after rupture. Interestingly, the oppo-

site was found recently in ruptured human

ACLs, compared to non-ruptured ACLs, with

a reduction in collagen and proteoglycans con-

tent noted. The authors suggested that these

changes occurred before or very soon after

rupture. However, the non-ruptured ligaments

were collected from aged donors during total

knee replacement, and may not indicate normal

ECM levels (Younget al. 2011).

Ruptured CrCLs also contain greater num-

bers of cells with the proteinases TRAP and

75.0

72.5

70.0

67.5

65.0

Ruptured CrCLs Intact CrCLs

Temperature (

°C)

p = 0.004

Figure 8.3 Dot diagram of the maximum temperature of

denaturation determined via differential scanning

calorimetry in eight ruptured and 11 intact cranial

cruciate ligaments (CrCLs) from 19 dogs. Horizontal lines

represent the mean values of each data set. Source:

Comerfordet al. 2004. Reproduced with permission from

the American Veterinary Medical Association.