Joint loads resulting in ACL rupture: Effects of age, sex, and body mass on injury load and mode of failure in a mouse model

Blaker, C.; Little, Christopher B.; Clarke, Elizabeth C.

doi:10.1002/jor.23418

Cited by 21 publications

(26 citation statements)

References 48 publications

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“…Fig. S1) as previously reported for other non‐invasive mouse models that recapitulate isolated ACL ruptures …”

Section: Methodssupporting

confidence: 85%

“…Our current study used a single load with a degree of rotational force to load the ACL to failure without obvious damage to the surrounding joint tissues, thus recapitulating an isolated ACL rupture injury which accounts for 18–40% of human cases . This is in keeping with other non‐invasive mouse models that recapitulate isolated ACL ruptures . This non‐invasive simple to implement, highly reproducible model of PTOA displays reliable and consistent OA pathology (only six animals are required to show effects with 80% power, p < 0.05).…”

Section: Discussionmentioning

confidence: 54%

“…It also facilitates identification of early initiating factors post‐injury and associated biomarkers, which may allow for stratification of patients to specific therapies in the future. To date, only a few studies have correlated the very early molecular, cellular and degenerative changes that occur within the mouse joint after ACL rupture [reviewed in], with the majority describing the architectural changes that occur within the musculoskeletal structures . The current study provides a timeline of changes in inflammatory mediators and details the compartmental degenerative changes that result from the injury allowing the potential points of intervention to be unveiled (Fig.…”

Section: Discussionmentioning

confidence: 99%

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

Gilbert

Bonnet

Stadnik

et al. 2018

Journal Orthopaedic Research

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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 36:2118–2127, 2018.

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“…Fig. S1) as previously reported for other non‐invasive mouse models that recapitulate isolated ACL ruptures …”

Section: Methodssupporting

confidence: 85%

Section: Discussionmentioning

confidence: 54%

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

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

Gilbert

Bonnet

Stadnik

et al. 2018

Journal Orthopaedic Research

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“…Additionally, this study only used male rats. Although sex has been shown to influence the mode of ACL rupture in mice and the severity of PTOA development in some surgical models, in a recent study of non‐invasive ACL rupture, pathological changes to joint tissue structure were determined to be sex‐independent . Last, changes to animal gait can influence disease progression but were not measured in this study.…”

Section: Discussionmentioning

confidence: 99%

Characterization of Post‐Traumatic Osteoarthritis in Rats Following Anterior Cruciate Ligament Rupture by Non‐Invasive Knee Injury (NIKI)

Brown

Hornyak

Jungels

et al. 2019

Journal Orthopaedic Research

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Small animal models are essential for studying anterior cruciate ligament (ACL) injury, one of the leading risk factors for post-traumatic osteoarthritis (PTOA). Non-surgical models of ACL rupture have recently surged as a new tool to study PTOA, as they circumvent the confounding effects of surgical disruption of the joint. These models primarily have been explored in mice and rabbits, but are relatively understudied in rats. The purpose of this work was to establish a non-invasive, mechanical overload model of ACL rupture in the rat and to study the disease pathogenesis following the injury. ACL rupture was induced via non-invasive tibial compression in Lewis rats. Disease state was characterized for 4 months after ACL rupture via histology, computed tomography, and biomarker capture from the synovial fluid. The non-invasive knee injury (NIKI) model created consistent ACL ruptures without direct damage to other tissues and resulted in conventional OA pathology. NIKI knees exhibited structural changes as early as 4 weeks post-injury, including regional structural changes to cartilage, chondrocyte and cartilage disorganization, changes to the bone architecture, synovial hyperplasia, and the increased presence of biomarkers of cartilage fragmentation and pro-inflammatory cytokines. These results suggest that this model can be a valuable tool to study PTOA. By establishing the fundamental pathogenesis of this injury, additional opportunities are created to evaluate unique contributing factors and potential therapeutic interventions for this disease. METHODS NIKI Device Design and Injury Loading SchemeThe NIKI device induces an ACL tear in the supine rat with the foot and knee secured in custom fixtures, as 356 JOURNAL OF ORTHOPAEDIC RESEARCH ® FEBRUARY 2020

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“…Muscle mass decreases age-dependently in part due to decreasing levels of IGF-1 20 , which results in joint instability and subsequent osteoarthritis development in patients 21–23 . Joint instability established by surgical dissection of the anterior cruciate ligament (ACL) is commonly used as an animal model of mechanical stress-induced osteoarthritis 24 . Mechanical loading due to obesity is also a risk factor for osteoarthritis development 25,26 .…”

Section: Introductionmentioning

confidence: 99%

Oral administration of N-acetyl cysteine prevents osteoarthritis development and progression in a rat model

Kaneko

Tanigawa

Sato

et al. 2019

Sci Rep

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The number of osteoarthritis patients is increasing with the rise in the number of elderly people in developed countries. Osteoarthritis, which causes joint pain and deformity leading to loss of activities of daily living, is often treated surgically. Here we show that mechanical stress promotes accumulation of reactive oxygen species (ROS) in chondrocytes in vivo, resulting in chondrocyte apoptosis and leading to osteoarthritis development in a rat model. We demonstrate that mechanical stress induces ROS accumulation and inflammatory cytokine expression in cultured chondrocytes in vitro and that both are inhibited by treatment with the anti-oxidant N-acetyl cysteine (NAC). In vivo, osteoarthritis development in a rat osteoarthritis model was also significantly inhibited by oral administration of NAC. MMP13 expression and down-regulation of type II collagen in chondrocytes, both of which indicate osteoarthritis, as well as chondrocyte apoptosis in osteoarthritis rats were inhibited by NAC. Interestingly, osteoarthritis development in sham-operated control sides, likely due to disruption of normal weight-bearing activity on the control side, was also significantly inhibited by NAC. We conclude that osteoarthritis development in rats is significantly antagonized by oral NAC administration. Currently, no oral medication is available to prevent osteoarthritis development. Our work suggests that NAC may represent such a reagent and serve as osteoarthritis treatment.

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Joint loads resulting in ACL rupture: Effects of age, sex, and body mass on injury load and mode of failure in a mouse model

Cited by 21 publications

References 48 publications

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

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

Characterization of Post‐Traumatic Osteoarthritis in Rats Following Anterior Cruciate Ligament Rupture by Non‐Invasive Knee Injury (NIKI)

Oral administration of N-acetyl cysteine prevents osteoarthritis development and progression in a rat model

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