Divergent roles of prostacyclin and PGE2 in human tendinopathy

Filip Bergqvist,Bridget Watkins,Stephanie G Dakin,Andrew J Carr,Kim Wheway,Udo Oppermann,Per-Johan Jakobsson

doi:10.1186/s13075-019-1855-5

Abstract

BackgroundTendon disease is a significant global healthcare burden whereby patients experience pain and disability; however, the mechanisms that underlie inflammation and pain are poorly understood. Herein, we investigated the role of prostaglandins as important mediators of inflammation and pain in tissues and cells derived from patients with tendinopathy.MethodsWe studied supraspinatus and Achilles tendon biopsies from symptomatic patients with tendinopathy or rupture. Tendon-derived stromal cells (CD45negCD34neg) isolated from tendons were cultured and treated with interleukin-1β (IL-1β) to investigate prostaglandin production.ResultsDiseased tendon tissues showed increased expression of prostacyclin receptor (IP) and enzymes catalyzing the biosynthesis of prostaglandins, including cyclooxygenase-1 (COX-1), COX-2, prostacyclin synthase (PGIS), and microsomal prostaglandin E synthase-1 (mPGES-1). PGIS co-localized with cells expressing Podoplanin, a marker of stromal fibroblast activation, and the nociceptive neuromodulator NMDAR-1. Treatment with IL-1β induced release of the prostacyclin metabolite 6-keto PGF1α in tendon cells isolated from diseased supraspinatus and Achilles tendons but not in cells from healthy comparator tendons. The same treatment induced profound prostaglandin E2 (PGE2) release in tendon cells derived from patients with supraspinatus tendon tears. Incubation of IL-1β treated diseased tendon cells with selective mPGES-1 inhibitor Compound III, reduced PGE2, and simultaneously increased 6-keto PGF1α production. Conversely, COX blockade with naproxen or NS-398 inhibited both PGE2 and 6-keto PGF1α production. Tendon biopsies from patients in whom symptoms had resolved showed increased PTGIS compared to biopsies from patients with persistent tendinopathy.ConclusionsOur results suggest that PGE2 sustains inflammation and pain while prostacyclin may have a protective role in human tendon disease.

Highlights

Inflammatory and fibrotic diseases of the joint are a significant cause of pain and impaired physical function [1]
We investigated expression of enzymes implicated in the production of prostaglandins including prostacyclin and prostaglandin E2 (PGE2) in tendon tissues collected from patients with tendinopathy compared to those from healthy volunteers
Prostacyclin synthase (PGIS) expression was identified in vascular regions (CD31posCD34pos), this protein was highly expressed by CD31negCD34neg cells with fibroblast-like morphology, identified to be resident tendon stromal cells

Summary

Introduction

Inflammatory and fibrotic diseases of the joint are a significant cause of pain and impaired physical function [1]. Inflammatory processes are increasingly recognized to contribute to the onset and progression of tendinopathy [2, 3], the precise mechanisms driving inflammation and pain associated with disease remain to be fully elucidated. Current therapeutic regimens include non-steroidal anti-inflammatory drugs (NSAIDs), glucocorticoids, or use of biological therapies including platelet-rich plasma in association with prolonged physical rehabilitation. Long-term use of glucocorticoids or NSAIDs is associated with adverse effects including tendon rupture [4,5,6] and impaired healing [7, 8]. Improved understanding of the biological mechanisms driving inflammation and pain are required to inform development of effective new treatments targeting cells driving tendon disease. We investigated the role of prostaglandins as important mediators of inflammation and pain in tissues and cells derived from patients with tendinopathy

Methods

Results

Discussion

Conclusion