Divergent roles of prostacyclin and PGE2 in human tendinopathy.

Background Tendon 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. Methods We 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-1andbeta; (IL-1andbeta;) to investigate prostaglandin production. Results Diseased 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-1andbeta; induced release of the prostacyclin metabolite 6-keto PGF1andalpha;andnbsp;in tendon cells isolated from diseased supraspinatus and Achilles tendons but not in cells from healthy comparator tendons. The same treatment induced profound prostaglandin E2andnbsp;(PGE2) release in tendon cells derived from patients with supraspinatus tendon tears. Incubation of IL-1andbeta; treated diseased tendon cells with selective mPGES-1 inhibitor Compound III, reduced PGE2, and simultaneously increased 6-keto PGF1andalpha;andnbsp;production. Conversely, COX blockade with naproxen or NS-398 inhibited both PGE2andnbsp;and 6-keto PGF1andalpha;production. Tendon biopsies from patients in whom symptoms had resolved showed increasedandnbsp;PTGISandnbsp;compared to biopsies from patients with persistent tendinopathy. Conclusions Our results suggest that PGE2andnbsp;sustains inflammation and pain while prostacyclin may have a protective role in human tendon disease.