Systemic EP4 Inhibition Increases Adhesion Formation in a Murine Model of Flexor Tendon Repair.

Geary, Michael B

Orner, Caitlin A

Bawany, Fatima

Awad, Hani A

Hammert, Warren C

O'Keefe, Regis J

Loiselle, Alayna E

Philp, Andrew

2023-10-01T14:45:01Z

2023-10-01T14:45:01Z

2015-01

2023-10-01T14:44:58Z

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.

PONE-D-15-17149

1932-6203

1932-6203

https://hdl.handle.net/10161/29053

eng

Public Library of Science (PLoS)

PloS one

10.1371/journal.pone.0136351

Tendons

Animals

Mice

Tendon Injuries

Disease Models, Animal

Collagen Type I

Dinoprostone

Signal Transduction

Gene Expression Regulation

Female

Matrix Metalloproteinase 2

Matrix Metalloproteinase 9

Receptors, Prostaglandin E, EP4 Subtype

Collagen Type I, alpha 1 Chain

Systemic EP4 Inhibition Increases Adhesion Formation in a Murine Model of Flexor Tendon Repair.

Journal article

Hammert, Warren C|0000-0001-7767-4124

e0136351

8

Duke

School of Medicine

Clinical Science Departments

Orthopaedic Surgery

Surgery

Surgery, Plastic, Maxillofacial, and Oral Surgery

Published

10