Cartographier la progression de l’arthrose du genou après une rupture non invasive du LCA

INTRODUCTION: Traumatic injuries of the anterior cruciate ligament (ACL) pose a
significant health concern due to the subsequent impairing pathological changes
occurring within synovial joints. Osteoarthritis (OA) often develops in the
knee after ACL tears and the medial anterior region of the knee is particularly
vulnerable to cartilage degeneration as this area experiences increased varus
torque in ACL-deficient knees (Ohori et al., 2017). Using a non-invasive in
vivo ACL rupture in rat model, this study first aims to understand the
temporal progression of OA at 4- and 7-weeks following ACL rupture, shedding
light on the underlying pathophysiological mechanisms while making the medial
anterior region a focal point of analysis. Secondly, this in vivo model
was also used to investigate the ability of a standard-of-care intra-articular
(IA) treatment to mitigate the progression of post-traumatic OA.

METHODS: In
adherence to the Canadian guidelines for animal care and experimentation, a
total of seventeen 14-week-old female Lewis rats were used in this study and
distributed in two cohorts. The first cohort (T1) encompassed five animals, one
served as a Control, while the remaining four underwent non-invasive ACL
rupture in their right hindlimb and were euthanized 4-weeks after injury. For the
second cohort (T2), twelve rats were divided into three groups of 4 animals: a
Control group, an ACL Rupture Non-Treated group, and an ACL Rupture IA-Treated
group. Eight rats underwent the non-invasive ACL rupture procedure in their
left hindlimb. The Control group were euthanized 4-weeks after the start of the
experiments, while the remaining were kept for an additional 3 weeks during
which the ACL Rupture IA-treated group received weekly IA-injections of a Hyaluronan-based
product. Non-invasive ACL rupture was achieved through a tibial compression
method (Figure 1) through the application of a rapid vertical
displacement of 2 mm at 8 mm/s to the flexed hindlimb of each anesthetized
animal. Immediately following injury, the ACL rupture was ascertained through
anterior drawer test, and later confirmed with joint dissection performed
during necropsy. At necropsy, femoral condyles and tibial plateaus were
collected and submitted fresh to mechanical characterization via normal
indentation and thickness mapping of the articular cartilage using a mechanical
tester (Mach-1v500css, Biomomentum). This assessment yielded mechanical
data on cartilage thickness and instantaneous modulus (IM) acquired from 30-40
distinct positions on each cartilage surface. Statistical analyses were
executed using the linear model with R software.

RESULTS: Mechanical testing results showed that the medial anterior femoral condyle in ACL ruptured joints had
a notable increase in thickness observed at 4 weeks post-injury (Rupture T1)
when compared to Control (p = 0.0035). Moreover, a subsequent
significant reduction in thickness can be observed between the 4-week T1 and
7-week T2 post-injury Non-Treated groups (p = 0.0077). The Rupture T2
Non-Treated group is also accompanied with a significantly higher instantaneous
modulus when compared to Control (p < 0.0001, Figure 2A&B).
The Rupture T2 IA-treated group exhibited significant differences only when
compared to the Rupture T2 Non-Treated group, with statistical significance
established for both thickness (p = 0.0067) and IM (p = 0.0006).
In the tibial plateaus, a noteworthy increase in thickness was only evident at
the 7-week post-rupture mark (Control vs Rupture T2 Non-Treated, p < 0.0001) along with a significantly lower IM in comparison to the Control group (p = 0.0301) and the Rupture T1 group (p = 0.0366, Figure
2C&D). Furthermore, at the 7-week mark (T2),
the IA-Treated group displayed comparable cartilage thickness to Control
compared to the Non-Treated group (p = 0.0215). Colormaps of the
cartilage surfaces (Figure 3) also evidently show that the instantaneous
modulus of the condyle at 7 weeks when the injury is not treated is much higher
than all other groups, while the stiffness of the anterior region of the tibial
plateaus decreases.

DISCUSSION: This study revealed
compelling insights into the temporal progression of cartilage degradation in
the anterior regions of both the femoral condyles and tibial plateaus following
ACL rupture. The study demonstrated that, at 4 weeks post-rupture, the condyles’
cartilage displayed signs of swelling, indicative of early onset OA. In
contrast, the 7-week timepoint unveiled a considerably more advanced stage of
cartilage degeneration with notable increase in stiffness, signaling a
transition into a medium to severe OA state. In contrast, the administration of
IA-treatment appeared to exert a protective influence on the cartilage
following ACL rupture. This intervention not only mitigated the severity of OA
progression but also allowed articular cartilage to maintain properties like those
observed in the Control groups or in the 4-week post-ACL rupture group. These
findings underline the validity of this ACL rupture-induced OA model in
assessing the progression of the disease as well as the effectiveness of potential
treatments.

SIGNIFICANCE: This clinically relevant ACL injury model offers non-invasive means
to faithfully replicate the evolving pathological features of post-traumatic OA
over time and stands out as a powerful tool for efficiently screening potential
therapeutic interventions.