title: Systemic EP4 Inhibition Increases Adhesion Formation in a Murine Model of Flexor Tendon Repair.
abstract: Flexor tendon injuries are a common clinical problem, and repairs are frequently complicated by post-operative adhesions forming between the tendon and surrounding soft tissue. Prostaglandin E2 and the EP4 receptor have been implicated in this process following tendon injury; thus, we hypothesized that inhibiting EP4 after tendon injury would attenuate adhesion formation. A model of flexor tendon laceration and repair was utilized in C57BL/6J female mice to evaluate the effects of EP4 inhibition on adhesion formation and matrix deposition during flexor tendon repair. Systemic EP4 antagonist or vehicle control was given by intraperitoneal injection during the late proliferative phase of healing, and outcomes were analyzed for range of motion, biomechanics, histology, and genetic changes. Repairs treated with an EP4 antagonist demonstrated significant decreases in range of motion with increased resistance to gliding within the first three weeks after injury, suggesting greater adhesion formation. Histologic analysis of the repair site revealed a more robust granulation zone in the EP4 antagonist treated repairs, with early polarization for type III collagen by picrosirius red staining, findings consistent with functional outcomes. RT-PCR analysis demonstrated accelerated peaks in F4/80 and type III collagen (Col3a1) expression in the antagonist group, along with decreases in type I collagen (Col1a1). Mmp9 expression was significantly increased after discontinuing the antagonist, consistent with its role in mediating adhesion formation. Mmp2, which contributes to repair site remodeling, increases steadily between 10 and 28 days post-repair in the EP4 antagonist group, consistent with the increased matrix and granulation zones requiring remodeling in these repairs. These findings suggest that systemic EP4 antagonism leads to increased adhesion formation and matrix deposition during flexor tendon healing. Counter to our hypothesis that EP4 antagonism would improve the healing phenotype, these results highlight the complex role of EP4 signaling during tendon repair.
authors: Center for Musculoskeletal Research, University of Rochester, Rochester, New York, United States of America; School of Medicine and Dentistry, University of Rochester, Rochester, New York, United States of America.
authors: Michael B
authors: MB
authors: Geary
authors: Center for Musculoskeletal Research, University of Rochester, Rochester, New York, United States of America; School of Medicine and Dentistry, University of Rochester, Rochester, New York, United States of America.
authors: Caitlin A
authors: CA
authors: Orner
authors: Center for Musculoskeletal Research, University of Rochester, Rochester, New York, United States of America.
authors: Fatima
authors: F
authors: Bawany
authors: Center for Musculoskeletal Research, University of Rochester, Rochester, New York, United States of America; Department of Biomedical Engineering, University of Rochester, Rochester, New York, United States of America.
authors: Hani A
authors: HA
authors: Awad
authors: Center for Musculoskeletal Research, University of Rochester, Rochester, New York, United States of America; Department of Orthopaedics and Rehabilitation, University of Rochester, Rochester, New York, United States of America.
authors: Warren C
authors: WC
authors: Hammert
authors: Center for Musculoskeletal Research, University of Rochester, Rochester, New York, United States of America.
authors: Regis J
authors: RJ
authors: O'Keefe
authors: Center for Musculoskeletal Research, University of Rochester, Rochester, New York, United States of America; Department of Orthopaedics and Rehabilitation, University of Rochester, Rochester, New York, United States of America.
authors: Alayna E
authors: AE
authors: Loiselle
mesh_terms: D000818:Animals; D024042:Collagen Type I / Q000096:biosynthesis; D000090602:Collagen Type I, alpha 1 Chain; D015232:Dinoprostone / Q000378:metabolism*; D004195:Disease Models, Animal; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D020778:Matrix Metalloproteinase 2 / Q000096:biosynthesis; D020780:Matrix Metalloproteinase 9 / Q000096:biosynthesis; D051379:Mice; D058309:Receptors, Prostaglandin E, EP4 Subtype / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D013708:Tendon Injuries / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D013710:Tendons / Q000378:metabolism* / Q000473:pathology
chemical_list: D024042:Collagen Type I; D000090602:Collagen Type I, alpha 1 Chain; D058309:Receptors, Prostaglandin E, EP4 Subtype; D020778:Matrix Metalloproteinase 2; C522362:Mmp2 protein, mouse; D020780:Matrix Metalloproteinase 9; C501830:Mmp9 protein, mouse; D015232:Dinoprostone