Biomechanical Characterization of a Model of Noninvasive, Traumatic Anterior Cruciate Ligament Injury in the Rat

Maerz, Tristan; Kurdziel, Michael D.; Davidson, Abigail A.; Baker, Kevin C.; Anderson, Kyle; Matthew, Howard W.T.

doi:10.1007/s10439-015-1292-9

Cited by 38 publications

(46 citation statements)

References 35 publications

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“…Evidence supporting the existence of underlying acute biologic phenomena at the time of ACL injury that precipitate rapid joint degeneration continues to emerge . In the present study, we applied high‐resolution 1 H‐NMR spectroscopy and DI‐MS to measure metabolite concentrations in the serum of rats subjected to a validated, non‐surgical ACL rupture protocol . We found that several carnitine and tryptophan metabolites distinguished ACLR from Control rats, and AUROC analysis of the top two LASSO regression‐identified metabolites at each time point demonstrated predictive accuracies of 76.8%, 96.8%, and 87.8% at 72 h, 4 weeks and 10 weeks, respectively.…”

Section: Discussionmentioning

confidence: 73%

“…Throughout the study, rats were allowed ad libitum cage activity and provided unlimited access to food and water. ACLR rats were subjected to a tibial compression‐based noninvasive ACL rupture protocol, as previously described . Briefly, rats were immobilized in prone position on a custom fixture on a materials testing system (Insight 5, MTS Systems, Eden Prairie, MN).…”

Section: Methodsmentioning

confidence: 99%

“…The right knee was flexed to 100° and constrained to restrict medial and lateral translation, and the right paw was mounted in 30° of dorsiflexion. After a preloading and preconditioning, a displacement of 3 mm was rapidly applied to the paw at a rate of 8 mm/s, causing anterior tibial subluxation and subsequent failure of the ACL . Anesthesia was induced with intraperitoneal ketamine/xylazine and maintained with 1–2% inhaled isoflurane.…”

Section: Methodsmentioning

confidence: 99%

“…In contrast, noninvasive injury models more accurately reproduce high‐energy joint loading and induce a closed, clinically relevant injury, representing a more useful tool to study metabolic pathways. Our group recently developed and characterized a tibial compression model to induce closed, isolated ACL rupture in the rat . This injury leads to drastic morphological tissue changes representative of PTOA .…”

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confidence: 99%

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Metabolomic serum profiling after ACL injury in rats: A pilot study implicating inflammation and immune dysregulation in post‐traumatic osteoarthritis

Maerz

Sherman

Newton

et al. 2018

Journal Orthopaedic Research

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ACL rupture is a major risk factor for post-traumatic osteoarthritis (PTOA) development. Little information exists on acute systemic metabolic indicators of disease development. Thirty-six female Lewis rats were randomized to Control or noninvasive anterior cruciate ligament rupture (ACLR) and to three post-injury time points: 72 h, 4 weeks, 10 weeks (n = 6). Serum was collected and analyzed by H nuclear magnetic resonance (NMR) spectroscopy and combined direct injection and liquid chromatography (LC)-mass spectrometry (MS)/MS (DI-MS). Univariate and multivariate statistics were used to analyze metabolomic data, and predictive biomarker models were analyzed by receiver operating characteristic (ROC) analysis. Topological pathway analysis was used to identify perturbed pathways. Two hundred twenty-two metabolites were identified by H NMR and DI-MS. Differences in the serum metabolome between ACLR and Control were dominated by medium- and long-chain acylcarnitine species. Further, decreases in several tryptophan metabolites were either found to be significantly different in univariate analysis or to play important contributory roles to multivariate model separation. In addition to acylcarnitines and tryptophan metabolites, glycine, carnosine, and D-mannose were found to differentiate ACLR from Control. Glycine, 9-hexadecenoylcarnitine, trans-2-Dodecenoylcarnitine, linoelaidyl carnitine, hydroxypropionylcarnitine, and D-Mannose were identified as biomarkers with high area under ROC curve values and high predictive accuracies. Our analysis provides new information regarding the potential contribution of inflammatory processes and immune dysregulation to the onset and progression of PTOA following ACL injury. As these processes have most commonly been associated with inflammatory arthropathies, larger-scale studies elucidating their involvement in PTOA development and progression are necessary. © 2018 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 36:1969-1979, 2018.

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Section: Discussionmentioning

confidence: 73%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

mentioning

confidence: 99%

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Metabolomic serum profiling after ACL injury in rats: A pilot study implicating inflammation and immune dysregulation in post‐traumatic osteoarthritis

Maerz

Sherman

Newton

et al. 2018

Journal Orthopaedic Research

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“…Immediately prior to injury, rats were administered 5 mg/kg subcutaneous Carprofen, anesthetized with intraperitoneal ketamine/xylazine, and maintained under 1-2% inhaled isoflurane. Noninvasive ACLR was induced using tibial compression-based mechanical loading, as previously described 25-27 . Rats were positioned prone on a custom fixture, with the right knee in ∼100° of flexion.…”

Section: Methodsmentioning

confidence: 99%

Traumatic Joint Injury Induces Acute Catabolic Bone Turnover Concurrent with Articular Cartilage Damage in a Rat Model of Post-Traumatic Osteoarthritis

Maerz

Newton

Fleischer

et al. 2020

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24Objective: Assess acute alterations in bone turnover, microstructure, and histomorphometry following 25 noninvasive anterior cruciate ligament rupture (ACLR). 26Methods: Twelve female Lewis rats were randomized to receive noninvasive ACLR or Sham loading 27 (n=6/group). In vivo μCT was performed at 3, 7, 10, and 14 days post-injury to quantify compartment-28 dependent subchondral (SCB) and epiphyseal trabecular bone remodeling. Near-infrared (NIR) molecular 29imaging was used to measure in vivo bone anabolism (800 CW BoneTag) and catabolism (Cat K 680 30 FAST). Metaphyseal bone remodeling and articular cartilage morphology was quantified using ex vivo 31 μCT and contrast-enhanced µCT, respectively. Calcein-based dynamic histomorphometry was used to 32 quantify bone formation. OARSI scoring was used to assess joint degeneration, and osteoclast number 33 was quantified on TRAP stained-sections. 34Results: ACLR induced acute catabolic bone remodeling in subchondral, epiphyseal, and metaphyseal 35 compartments. Thinning of medial femoral condyle (MFC) SCB was observed as early as 7 days post-36 injury, while lateral femoral condyles (LFC) exhibited SCB gains. Trabecular thinning was observed in 37 MFC epiphyseal bone, with minimal changes to LFC. NIR imaging demonstrated immediate and 38 sustained reduction of bone anabolism (~15-20%), and a ~32% increase in bone catabolism at 14 days, 39 compared to contralateral limbs. These findings were corroborated by reduced bone formation rate and 40 increased osteoclast numbers, observed histologically. ACLR-injured femora had significantly elevated 41 OARSI score, cartilage thickness, and cartilage surface deviation. 42 Conclusion: ACL rupture induces immediate and sustained reduction of bone anabolism and 43 overactivation of bone catabolism, with mild-to-moderate articular cartilage damage at 14 days post-44 injury. 45 46 47 INTRODUCTION: 48 Post-traumatic osteoarthritis (PTOA) is a degenerative joint condition known to develop 49 following traumatic joint injuries. Anterior cruciate ligament (ACL) rupture is associated with a 50 particularly high risk for PTOA developmentapproximately 50% of patients develop PTOA 51 10-15 years after ACL rupture 1-3 . Surgical ACL reconstruction is a successful treatment to 52 alleviate pain and restore joint stability and function, but despite excellent patient-reported 53 outcomes and a high return-to-sport incidence, reconstruction has not been definitively shown to 54 alter the natural history of PTOA 2, 4, 5 . This observation has led to the hypothesis that acute 55 biological events initiated post-injury play a key role in the onset and progression of PTOA, as 56 opposed to primarily chronic joint instability. These biological events, their respective 57 contribution to PTOA pathogenesis, and the mechanisms that regulate them remain poorly 58 understood. 59 Crosstalk between articular cartilage (AC) and bone is an important component of 60 healthy joint homeostasis. AC and underlying bone interact via biochemical and mechanical 61...

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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

2016

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Anterior cruciate ligament (ACL) tears are a common knee injury with a known but poorly understood association with secondary joint injuries and post-traumatic osteoarthritis (OA). Female sex and age are known risk factors for ACL injury but these variables are rarely explored in mouse models of injury. This study aimed to further characterize a non-surgical ACL injury model to determine its clinical relevance across a wider range of mouse specifications. Cadaveric and anesthetized C57BL/6 mice (9-52 weeks of age) underwent joint loading to investigate the effects of age, sex, and body mass on ACL injury mechanisms. The ACL injury load (whole joint load required to rupture the ACL) was measured from force-displacement data, and mode of failure was assessed using micro-dissection and histology. ACL injury load was found to increase with body mass and age (p < 0.001) but age was not significant when controlling for mass. Sex had no effect. In contrast, the mode of ACL failure varied with both age and sex groups. Avulsion fractures (complete or mixed with mid-substance tears) were common in all age groups but the proportion of mixed and mid-substance failures increased with age. Females were more likely than males to have a major avulsion relative to a mid-substance tear (p < 0.01). This data compliments studies in human cadaveric knees, and provides a basis for determining the severity of joint injury relative to a major ACL tear in mice, and for selecting joint loading conditions in future experiments using this model. © 2016 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 35:1754-1763, 2017.

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Biomechanical Characterization of a Model of Noninvasive, Traumatic Anterior Cruciate Ligament Injury in the Rat

Cited by 38 publications

References 35 publications

Metabolomic serum profiling after ACL injury in rats: A pilot study implicating inflammation and immune dysregulation in post‐traumatic osteoarthritis

Metabolomic serum profiling after ACL injury in rats: A pilot study implicating inflammation and immune dysregulation in post‐traumatic osteoarthritis

Traumatic Joint Injury Induces Acute Catabolic Bone Turnover Concurrent with Articular Cartilage Damage in a Rat Model of Post-Traumatic Osteoarthritis

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

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