A novel rat model for subchondral microdamage in acute knee injury: a potential mechanism in post-traumatic osteoarthritis

Ramme, Austin J.; Lendhey, Matin; Raya, José G.; Kirsch, Thorsten; Kennedy, Oran D.

doi:10.1016/j.joca.2016.05.017

Cited by 40 publications

(41 citation statements)

References 56 publications

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“…We chose this model in rats because of the technical ease in injecting the knees of these animals and because correction of an induced lesion would better mimic the situation in humans. The procedure was performed under anesthesia (1–3% isoflurane) as previously described68. All experimental groups of rats, as described below, consisted of 3 rats and each experimental group was repeated once (total of 6 rats per experimental group).…”

Section: Methodsmentioning

confidence: 99%

Endogenous adenosine maintains cartilage homeostasis and exogenous adenosine inhibits osteoarthritis progression

et al. 2017

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Osteoarthritis (OA) is characterized by cartilage destruction and chondrocytes have a central role in this process. With age and inflammation chondrocytes have reduced capacity to synthesize and maintain ATP, a molecule important for cartilage homeostasis. Here we show that concentrations of ATP and adenosine, its metabolite, fall after treatment of mouse chondrocytes and rat tibia explants with IL-1β, an inflammatory mediator thought to participate in OA pathogenesis. Mice lacking A2A adenosine receptor (A2AR) or ecto-5′nucleotidase (an enzyme that converts extracellular AMP to adenosine) develop spontaneous OA and chondrocytes lacking A2AR develop an ‘OA phenotype' with increased expression of Mmp13 and Col10a1. Adenosine replacement by intra-articular injection of liposomal suspensions containing adenosine prevents development of OA in rats. These results support the hypothesis that maintaining extracellular adenosine levels is an important homeostatic mechanism, loss of which contributes to the development of OA; targeting adenosine A2A receptors might treat or prevent OA.

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Section: Methodsmentioning

confidence: 99%

Endogenous adenosine maintains cartilage homeostasis and exogenous adenosine inhibits osteoarthritis progression

et al. 2017

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“…In the last 10 years, multiple non‐invasive ACL rupture models have been developed. These models have primarily used mice and rabbits, with a limited number of studies involving rats . Despite being relatively understudied, there are advantages to establishing this injury model in rats, such as their amenability to behavioral tests and their larger size, which can accommodate certain imaging modalities and therapeutic interventions .…”

mentioning

confidence: 99%

“…Despite being relatively understudied, there are advantages to establishing this injury model in rats, such as their amenability to behavioral tests and their larger size, which can accommodate certain imaging modalities and therapeutic interventions . Even within the few studies using rats, different structural outcomes have been observed following ACL rupture, ranging from cartilage degeneration to cartilage thickening . Additionally, the characterization of the inflammatory response to this injury has been scarcely studied, with only one recent evaluation of immune cell involvement and cytokine profile following injury in mice reported .…”

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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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“…The authors contrast these methods and note that each provides an opportunity to study a particular aspect of PTOA . Our laboratory has developed a noninvasive rat model, which provides an opportunity to study subchondral microdamage . Using this model, we can determine the role of microdamage and its subsequent repair by remodeling in PTOA development via altered bone/cartilage crosstalk.…”

Section: Animal Models For Ptoamentioning

confidence: 99%

“…64 Our laboratory has developed a noninvasive rat model, which provides an opportunity to study subchondral microdamage. 69 Using this model, we can determine the role of microdamage and its subsequent repair by remodeling in PTOA development via altered bone/cartilage crosstalk. Other research groups have also used the rat for OA studies, inducing joint disease by surgical intervention or by ACL rupture.…”

Section: Animal Models For Ptoamentioning

confidence: 99%

The role of subchondral bone damage in post‐traumatic osteoarthritis

Coughlin

Kennedy

2016

Annals of the New York Academy of Sciences

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Osteoarthritis (OA), the most common musculoskeletal disease in the United States, is characterized by cartilage breakdown, pain, and restricted movement. Post-traumatic OA (PTOA) occurs subsequent to traumatic joint injury, such as anterior cruciate ligament (ACL) rupture, and makes up 12% of the overall disease burden, with healthcare costs of approximately $3 billion/year. The current paradigm for PTOA is based on the observation that joint injury affects multiple tissues, all of which may contribute to subsequent joint failure. Subchondral bone plays a significant role in PTOA, as shown by magnetic resonance imaging evidence that subchondral bone marrow lesions (BMLs) are present in 80% of ACL rupture cases immediately after joint injury. The presence of BMLs indicates an acute consequence of injury, specifically in subchondral bone, which could be targeted with preventative therapy. BMLs may be a direct representation of physical damage to bone tissue. Interestingly, microdamage is known to induce osteoclast-mediated remodeling in bone. Furthermore, the contiguous link between subchondral bone and articular cartilage may allow transport of small molecules, resulting from these remodeling processes, to cross the osteochondral junction and contribute to PTOA development. Targeting subchondral bone by inhibiting subchondral remodeling, particularly in the early phase postinjury, may be a potential approach for preventing PTOA.

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A novel rat model for subchondral microdamage in acute knee injury: a potential mechanism in post-traumatic osteoarthritis

Abstract: This study shows that our novel model can be used to study subchondral microdamage after ACL-rupture, and its association with localized remodeling. Cartilage degeneration, on a similar time-scale to other models, is also a feature of this system.

Cited by 40 publications

References 56 publications

Endogenous adenosine maintains cartilage homeostasis and exogenous adenosine inhibits osteoarthritis progression

Endogenous adenosine maintains cartilage homeostasis and exogenous adenosine inhibits osteoarthritis progression

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

The role of subchondral bone damage in post‐traumatic osteoarthritis

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