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.
Highlights
Flexor tendons (FT) in the hand run on the palmar side of the digits and transmit the forces that allow for finger flexion
An intrasynovial flexor digitorum longus (FDL) tendon repair model was used in untreated mice to determine the expression profile of EP4 (Ptger4), which would inform the timing for EP4 antagonist treatment in the study groups (Fig 1A)
As such, quantifying cAMP levels in the repair site from EP4 antagonist and vehicle treated mice would indicate whether EP4 signaling was effectively inhibited in the antagonist group
Summary
Flexor tendons (FT) in the hand run on the palmar side of the digits and transmit the forces that allow for finger flexion. Fibrous adhesions between the tendon and surrounding tissue form to some extent in all cases of tendon repair, and up to 30– 40% of cases are significant enough to result in loss of digit range of motion (ROM) and impaired hand function [5]. There are more than 30,000 tendon repair procedures a year in the US, with billions in associated healthcare costs [6]. Given this clinical challenge, there is significant interest in optimizing the repair process to improve functional outcomes following FT injury. One area of interest for improving FT repair is the fibrous adhesions that form as a result of excessive inflammation around the injury site [1, 9, 10]. Attenuating ECM deposition after injury is an apt target for improving outcomes after FT surgery
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