Elbow trauma and plasminogen deficiency showing functional deficits in an animal model
Sandra Susanne Gebhart, MD1; Jon Schoenecker, MD, PhD1; Mihir J Desai, MD1; Stephanie N Moore, MS2; William Oelsner, BS3; (1)Vanderbilt Orthopaedics, Nashville, TN, (2)Vanderbilt University, Nashville, TN, (3)Medical University of South Carolina, Charelston, SC
BACKGROUND: Elbow stiffness and loss of motion is a debilitating condition, precluding patients from performing activities from daily living. Previous investigations of heterotopic ossification and joint contracture of the elbow in animal models have focused on local contributions to elbow stiffness, thereby underscoring the variety of clinical scenarios in which HO, fibrosis, and impaired range of motion can develop. Recently, our lab has determined that plasmin, the pain protease of the fibrinolytic system is essential for virtually all tissue repair processes including the inhibition of calcification of damaged skeletal muscle following trauma. Therefore, we hypothesize that systemic changes in plasminogen, the zymogen of plasmin, in combination with a large tissue injury to the peri-elbow musculature, will results in impaired elbow function and stiffness.
Methods: Investigator induced plasminogen deficiency was accomplished via targeted antisense oligonucleotide administration. Mice underwent cardiotoxin-induced peri-elbow muscle injury at 6 weeks of age. Histological analysis, quantification of skeletal muscle calcification and HO, assessment of fibrosis, and functional testing was performed 28 days following injury.
Results: Loss of plasminogen, in combination with peri-elbow skeletal muscle injury resulted in delayed skeletal muscle repair, fibrosis, and chronic inflammation. Skeletal muscle endochondral ossification was observed within damaged tissues. Finally, we observed a detectable loss of upper extremity function, phenocopying the functional changes observed in the clinic.
CONCLUSIONS: This model represents a validated, reliable, preclinical model that phenocopies the human disease. To our knowledge, this is the first reproducible, clinically relevant upper extremity animal model of elbow stiffness that involves meaningful functional outputs.
CLINICAL RELIVENCE: Given the well described hypofibrinolytic state experienced by trauma patients, this clinically relevant model provides the opportunity to examine potential therapeutics options for limiting upper extremity joint contracture and stiffness following injury. Moreover, by providing a direct link between plasminogen deficiency and impaired elbow function, this proof-of-concept investigation identifies a single pharmacologic target which, if enhanced may protect both elbow function and muscle regeneration following traumatic injury.
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