Abstract
BackgroundPeri-articular injury may result in functional deficits and pain. In particular, post-traumatic elbow stiffness is a debilitating condition, precluding patients from performing activities of daily living. As such, clinicians and basic scientists alike, aim to develop novel therapeutic interventions to prevent and treat elbow stiffness; thereby reducing patient morbidity. Yet, there is a paucity of pre-clinical models of peri-articular stiffness, especially of the upper extremity, necessary to develop and test the efficacy of therapeutics. We set out to develop a pre-clinical murine model of elbow stiffness, resulting from soft tissue injury, with features characteristic of pathology observed in these patients.MethodsA soft tissue peri-elbow injury was inflicted in mice using cardiotoxin. Pathologic tissue repair was induced by creating an investigator-imposed deficiency of plasminogen, a protease essential for musculoskeletal tissue repair. Functional testing was conducted through analysis of grip strength and gait. Radiography, microcomputed tomography, and histological analyses were employed to quantify development of heterotopic ossification.ResultsAnimals with peri-elbow soft tissues injury in conjunction with an investigator-imposed plasminogen deficiency, developed a significant loss of elbow function measured by grip strength (2.387 ± 0.136 N vs 1.921 ± 0.157 N, ****, p < 0.0001) and gait analysis (35.05 ± 2.775 mm vs 29.87 ± 2.075 mm, ***, p < 0.0002). Additionally, plasminogen deficient animals developed capsule thickening, delayed skeletal muscle repair, fibrosis, chronic inflammation, and heterotopic ossification; all features characteristic of pathology observed in patients with trauma-induced elbow stiffness.ConclusionA soft tissue injury to the peri-elbow soft tissue with a concomitant deficiency in plasminogen, instigates elbow stiffness and pathologic features similar to those observed in humans. This pre-clinical model is valuable for translational studies designed to investigate the contributions of pathologic features to elbow stiffness or as a high-throughput model for testing therapeutic strategies designed to prevent and treat trauma-induced elbow stiffness.
Highlights
Peri-articular injury may result in functional deficits and pain
The purpose of this work was to develop and validate a pre-clinical murine model of elbow stiffness, resulting from peri-elbow soft tissue injury, with features characteristic of pathology observed in patients
Peri-elbow soft tissue injury, in conjunction with an investigator-imposed plasminogen deficiency, results in a significant loss of elbow function Given that functional deficits following a peri-articular injury are a life altering event, we first assessed in our murine model if following a peri-elbow injury, in conjunction with an investigator-induced plasminogen deficiency, we could detect a change in upper extremity function
Summary
Peri-articular injury may result in functional deficits and pain. In particular, post-traumatic elbow stiffness is a debilitating condition, precluding patients from performing activities of daily living. The purpose of this work was to develop and validate a pre-clinical murine model of elbow stiffness, resulting from peri-elbow soft tissue injury, with features characteristic of pathology observed in patients. Given that both the degree of elbow stiffness (Brinsden et al 2008; King and Faber 2000; Mansat et al 2000) and plasmin activity reduction (Amaro et al 2017; Gibson et al 2017) have been related to the severity of injury, we examined if a focal peri-elbow soft tissue injury, in conjunction with an investigator-imposed plasminogen deficiency, was sufficient to model trauma-induced elbow stiffness
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