Advances in the Canine Cranial Cruciate Ligament, 2nd edition

Cruciate Ligament Matrix Metabolism and Development of Laxity 67

Cruciate ligament metabolism and

laxity in human beings and other

species

Ligament metabolism may affect ligament
strength, and it has been suggested that
upregulated anterior cruciate ligament (ACL)
remodeling may predispose women to ACL
injury (Foos et al. 2001). Hormonal factors
have been shown to play an important role in
ligament metabolism and increased anterior
knee laxity (Parket al. 2009). In a systematic
review (Hewettet al. 2007), it was demonstrated
that women were at risk for ACL injuries in
the first half or pre-ovulatory phase of their
menstrual cycle, with one recent study advising
that female athletes should not exercise aggres-
sively during this part of their cycle (Stijaket al.
2015). Estrogen and progesterone appear to
influence collagen metabolism in both animal
models and human beings. Estrogen (i.e., estra-
diol) has been shown to decrease fibroblast
proliferation and type I pro-collagen, whereas
progesterone counterbalances the inhibitory
effect of estrogen on female ACLs (Yuet al.
1999). Estrogen-primed ACL cells are also very
responsive to relaxin, decreasing collagen type
I and III gene expression as well increasing
the expression of degradative enzymes such as
MMP-1 and 3 (Konopkaet al. 2016).
Most studies concerning knee laxity have
been conducted on the ACL, and most have
involved ex vivo cadaveric testing.Ex vivo,
varus–valgus laxity and angulation is increased
greatly by sectioning the collateral ligaments
(Markolfet al. 1976). Anterior–posterior stabil-
ity is affected by the transection of most liga-
ments, with ACL sectioning showing the great-
est increase at full joint extension (Markolfet al.
1976). Varus–valgus and anteroposterior laxity
is thought to be an important contributor in the
pathogenesis of human knee arthritis (Sharma
et al. 1999). Increased laxity may contribute to
abnormal knee biomechanics and abnormally
distributed joint loads that likely lead to or
accelerate arthritis.
Increased knee laxity was demonstrated in
the ovulatory or post-ovulatory phases of the
female menstrual cycle (Zazulaket al. 2006; Park
et al. 2009; Leeet al. 2013). A significantly higher
anterior–posterior joint laxity and hyperexten-
sion has been identified in non-contact ACL

injury in females compared to males (Uhorchak

et al. 2003). Although studies have examined the

effects of sex hormones on ACL metabolism,

there are few reports of normal ACL ECM

remodeling/degradation and its relationship to

joint laxity.

It has been suggested that increased colla-

gen remodeling of the normal guinea pig ACL

by gelatinases (MMP-2 and MMP-9) may con-

tribute to ligament and, therefore, knee joint lax-

ity (Quasnichkaet al. 2005). Increased remodel-

ing was demonstrated in CrCLs from a strain

of guinea pigs predisposed to the development

of spontaneous arthritis (i.e., Dunkin Hartley) at

12 weeks compared to a control strain (i.e., Bris-

tol Strain-2). All of the biochemical and mechan-

ical changes in the predisposed CrCLs occurred

before subchondral bone and cartilage changes

at 24 weeks (Anderson-MacKenzieet al. 2005).

These studies suggest that increased remodel-

ing of the CrCL may contribute to ligament and,

therefore, knee joint laxity.

Canine cruciate ligament metabolism

and laxity

Introduction

Most interest in ECM degradation of canine

articular tissue has centered on the MMPs

(collagenases, stromelysins and gelatinases),

cathepsins (serine, cysteine and aspartic pro-

teases), and the ADAMTs family of enzymes.

The MMPs are regulated by several natural

inhibitors, such as the tissue inhibitors of met-

alloproteinases (TIMPs) andα 2 -macroglobulin,

in order to prevent excessive activity and result-

ing matrix degradation.

The collagenases (MMP-1, -8, and -13) (which

cleave the fibrillar collagens at a specific

site within their helical domain, generating

3/4 and 1/4 fragments) have been demon-

strated in normal and in experimental arthritic

canine cartilage (Fernandeset al. 1998). The

stromelysins (MMP-3 and -10) and gelatinases

(MMP-2 and -9) have been identified in canine

synovial fluid associated with experimentally

induced and rheumatoid arthritis, respectively

(Coughlan et al. 1998; Panula et al. 1998).

Increased concentrations of the N-terminal

(393) Alanine-Arginine-Glycine-Serine (ARGS)