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Inflammatory and degenerative phases resulting from anterior cruciate rupture in a non-invasive murine model of post-traumatic osteoarthritis.

ABSTRACT: Joint injury is the predominant risk factor for post-traumatic osteoarthritis development (PTOA). Several non-invasive mouse models mimicking human PTOA investigate molecular mechanisms of disease development; none have characterized the inflammatory response to this acute traumatic injury. Our aim was to characterize the early inflammatory phase and later degenerative component in our in vivo non-invasive murine model of PTOA induced by anterior cruciate ligament (ACL) rupture. Right knees of 12-week-old C57Bl6 mice were placed in flexion at a 30° offset position and subjected to a single compressive load (12N, 1.4?mm/s) to induce ACL rupture with no obvious damage to surrounding tissues. Tissue was harvested 4?h post-injury and on days 3, 14, and 21; contralateral left knees served as controls. Histological, immunohistochemical, and gene analyzes were performed to evaluate inflammatory and degenerative changes. Immunohistochemistry revealed time-dependent expression of mature (F4/80 positive) and inflammatory (CD11b positive) macrophage populations within the sub-synovial infiltrate, developing osteophytes, and inflammation surrounding the ACL in response to injury. Up-regulation of genes encoding acute pro-inflammatory markers, inducible nitric oxide synthase, interleukin-6 and interleukin-17, and the matrix degrading enzymes, ADAMTS-4 and MMP3 was detected in femoral cartilage, concomitant with extensive cartilage damage and bone remodelling over 21-days post-injury. Our non-invasive model describes pathologically distinct phases of the disease, increasing our understanding of inflammatory episodes, the tissues/cells producing inflammatory mediators and the early molecular changes in the joint, thereby defining the early phenotype of PTOA. This knowledge will guide appropriate interventions to delay or arrest disease progression following joint injury. © 2018 The Authors. Journal of Orthopaedic Research® Published by Wiley Periodicals, Inc. on behalf of the Orthopaedic Research Society. J Orthop Res 9999:1-10, 2018.

SUBMITTER: Gilbert SJ

PROVIDER: S-EPMC6120532 | biostudies-literature | 2018 Feb

REPOSITORIES: biostudies-literature

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Inflammatory and degenerative phases resulting from anterior cruciate rupture in a non-invasive murine model of post-traumatic osteoarthritis.

Gilbert Sophie J SJ Bonnet Cleo S CS Stadnik Paulina P Duance Victor C VC Mason Deborah J DJ Blain Emma J EJ

Journal of orthopaedic research : official publication of the Orthopaedic Research Society 20180217

Joint injury is the predominant risk factor for post-traumatic osteoarthritis development (PTOA). Several non-invasive mouse models mimicking human PTOA investigate molecular mechanisms of disease development; none have characterized the inflammatory response to this acute traumatic injury. Our aim was to characterize the early inflammatory phase and later degenerative component in our in vivo non-invasive murine model of PTOA induced by anterior cruciate ligament (ACL) rupture. Right knees of 1 ...[more]

PMID: 29453795

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Project description:BackgroundThe long-term prevalence of knee osteoarthritis (OA) after anterior cruciate ligament (ACL) injury is unknown, especially in patients without a history of ACL surgery.PurposeTo (1) describe the prevalence of radiographic OA, symptomatic OA, and knee replacement surgery 32 to 37 years after acute ACL injury and to (2) compare the prevalence of radiographic OA, symptomatic OA, and knee symptoms between patients allocated to early ACL surgery or no ACL surgery and patients who crossed over to ACL surgery.Study designCohort study; Level of evidence, 2.MethodsParticipants aged 15 to 40 years at the time of ACL injury were allocated to surgical (augmented or nonaugmented ACL repair) or nonsurgical ACL treatment within 14 days of injury. At 32 to 37 years after the initial injury, 153 participants were followed up with plain weightbearing radiographs and completed 4 subscales from the Knee injury and Osteoarthritis Outcome Score (KOOS). Radiographic OA was defined as Kellgren and Lawrence grade 2 or higher. Symptomatic OA was defined as radiographic OA plus knee symptoms measured with the KOOS.ResultsParticipants allocated to ACL surgery (n = 64) underwent surgery at a mean ± SD of 5 ± 4 days (range, 0-11 days) after injury. Of the 89 participants allocated to no ACL surgery, 53 remained nonsurgically treated, 27 had ACL surgery within 2 years, and 9 had ACL surgery between 3 and 21 years after injury. In the total sample, 95 participants (62%) had radiographic tibiofemoral OA, including 11 (7%) who had knee replacement. The prevalence of radiographic tibiofemoral OA was lower in the group allocated to ACL surgery compared with the group who never had ACL surgery (50% vs 75%; P = .005). The prevalence of symptomatic OA (50% in the total sample) and patellofemoral radiographic OA (35% in the total sample) was similar between groups.ConclusionPatients allocated to early ACL surgery, performed a mean 5 days after injury, had a lower prevalence of tibiofemoral radiographic OA at 32 to 37 years after injury compared with patients who never had ACL surgery. The prevalences of symptomatic OA, radiographic patellofemoral OA, and knee symptoms were similar irrespective of ACL treatment. Overall, the prevalence of OA after ACL injury was high.RegistrationNCT03182647 (ClinicalTrials.gov identifier).

Project description:Knee instability resulting from anterior cruciate ligament (ACL) rupture is a high-risk factor for posttraumatic osteoarthritis (PTOA) in the patellofemoral joint (PFJ). However, whether non-weight-bearing and weight-bearing treatments have chondroprotective effects remains unclear. Twenty-four adult New Zealand White male rabbits were employed in this study. All animals received ACL transection in the right knee and sham surgery in the left knee. The rabbits were randomly assigned to the following groups: (I) In the sedentary (SED) group, the rabbits (n = 6) were simply kept in their cage; (II) In the continuous passive motion (CPM) group, the rabbits (n = 6) performed CPM exercise for 7 days, starting from the first postoperative day; (III) In the active treadmill exercise (TRE) group, the rabbits (n = 6) performed TRE for 2 weeks; (IV) In the CPM + TRE group, the rabbits (n = 6) executed CPM exercise, followed by TRE. Two joint surfaces (the retropatella and femoral trochlear groove) were assessed at 4 weeks after operation. Although the gross appearance in each group was comparable, histological examination revealed significant differences in the articular cartilage status. The CPM group exhibited a greater thickness of articular cartilage, maintenance of tidemark continuity, abundant glycosaminoglycan (GAG), and significantly lower inflammatory cytokine 9, e.g., tumor necrosis factor-alpha (TNF-α) 0 levels, with modest cell apoptosis (i.e., caspase-3). By contrast, the TRE group displayed the worst pathological features: an irregular cartilage surface and chondrocyte disorganization, reduced cartilage thickness, breakdown of the tidemark, depletion of collagen fibers, loss of GAG, and the highest levels of TNF-α and caspase-3 expression. Furthermore, the CPM + TRE group had more favorable outcomes than the SED group, indicating that suitable exercise is needed. The sham treatment displayed no variance in the changes in the two joint surfaces among groups. These data indicate that the application of early CPM rehabilitation is suggested for subjects in order to decrease the risk of PTOA without ACL reconstruction in the PFJ compartment in rabbits. The early TRE program, however, had harmful outcomes. Additionally, inactivity was discovered to initiate the development of PTOA.

Project description:BackgroundAnterior cruciate ligament (ACL) graft rupture occurs at a high rate, especially in young athletes. The geometries of the tibial plateau and femoral intercondylar notch are risk factors for first-time ACL injury; however, little is known about the relationship between these geometries and risk of ACL graft rupture.HypothesisThe geometric risk factors for noncontact graft rupture are similar to those previously identified for first-time noncontact ACL injury, and sex-specific differences exist.Study designCase-control study; Level of evidence, 3.MethodsEleven subjects who suffered a noncontact ACL graft rupture and 44 subjects who underwent ACL reconstruction but did not experience graft rupture were included in the study. Using magnetic resonance imaging, the geometries of the tibial plateau subchondral bone, articular cartilage, meniscus, tibial spines, and femoral notch were measured. Risk factors associated with ACL graft rupture were identified using Cox regression.ResultsThe following were associated with increased risk of ACL graft injury in males: increased posterior-inferior-directed slope of the articular cartilage in the lateral tibial plateau measured at 2 locations (hazard ratio [HR] = 1.50, P = .029; HR = 1.39, P = .006), increased volume (HR = 1.45, P = .01) and anteroposterior length (HR = 1.34, P = .0023) of the medial tibial spine, and increased length (HR = 1.18, P = .0005) and mediolateral width (HR = 2.19, P = .0004) of the lateral tibial spine. In females, the following were associated with increased risk of injury: decreased volume (HR = 0.45, P = .02) and height (HR = 0.46, P = .02) of the medial tibial spine, decreased slope of the lateral tibial subchondral bone (HR = 0.72, P = .01), decreased height of the posterior horn of the medial meniscus (HR = 0.09, P = .001), and decreased intercondylar notch width at the anterior attachment of the ACL (HR = 0.72, P = .02).ConclusionThe geometric risk factors for ACL graft rupture are different for males and females. For females, a decreased femoral intercondylar notch width and a decreased height of the posterior medial meniscus were risk factors for ACL graft rupture that have also been found to be risk factors for first-time injury. There were no risk factors in common between ACL graft injury and first-time ACL injury for males.

Dataset Information

Inflammatory and degenerative phases resulting from anterior cruciate rupture in a non-invasive murine model of post-traumatic osteoarthritis.

Publications

Inflammatory and degenerative phases resulting from anterior cruciate rupture in a non-invasive murine model of post-traumatic osteoarthritis.

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