Prostaglandin E2/EP4 axis is upregulated in Spondyloarthritis and contributes to radiographic progression

Daniele Mauro; Archita Srinath; Giuliana Guggino; Vicky Nicolaidou; Stefania Raimondo; Jonathan J Ellis; Jessica Whyte; Maria Maddalena Nicoletti; Marco Romano; Tony John Kenna; Juan D Cañete; Riccardo Alessandro; Aroldo Rizzo; Matthew Arthur Brown; Nicole J Horwood; Nigil Haroon; Francesco Ciccia

doi:10.1016/j.clim.2023.109332

Prostaglandin E2/EP4 axis is upregulated in Spondyloarthritis and contributes to radiographic progression

Clin Immunol. 2023 Jun:251:109332. doi: 10.1016/j.clim.2023.109332. Epub 2023 Apr 17.

Authors

Daniele Mauro¹, Archita Srinath², Giuliana Guggino³, Vicky Nicolaidou⁴, Stefania Raimondo⁵, Jonathan J Ellis⁶, Jessica Whyte⁶, Maria Maddalena Nicoletti¹, Marco Romano⁷, Tony John Kenna⁶, Juan D Cañete⁸, Riccardo Alessandro⁵, Aroldo Rizzo⁹, Matthew Arthur Brown¹⁰, Nicole J Horwood¹¹, Nigil Haroon¹², Francesco Ciccia¹³

Affiliations

¹ Rheumatology Unit, Department of Precision Medicine, Università degli Studi della Campania "L. Vanvitelli", Naples, Italy.
² Schroeder Arthritis Institute, Krembil Research Institute, University Health Network, Toronto Western Hospital, University of Toronto, Toronto, Ontario, Canada.
³ Rheumatology Section, Department of Health Promotion, Mother and Child Care, Internal Medicine and Medical Specialties, University of Palermo, Italy.
⁴ Department of Life Sciences, School of Life and Health Sciences, University of Nicosia, Cyprus.
⁵ Dipartimento di Biomedicina, Neuroscienze e Diagnostica Avanzata, Università degli Studi di Palermo, Palermo, Italy.
⁶ Institute of Health and Biomedical Innovation, Queensland University of Technology, Woolloongabba, Queensland, Australia.
⁷ Hepato-Gastroenterology Unit, Department of Precision Medicine, Università degli Studi della Campania "L. Vanvitelli", Naples, Italy.
⁸ Department of Rheumatology, Hospital Clinic of Barcelona, 08036 Barcelona, Spain.
⁹ Dipartimento di Oncoematologia, Sezione di Anatomia Patologica, Azienda Ospedaliera Ospedali riuniti Villa Sofia Cervello, Palermo, Italy.
¹⁰ Department of Medical and Molecular Genetics, King's College London, London, UK.
¹¹ Norwich Medical School, University of East Anglia, Norwich, UK.
¹² Schroeder Arthritis Institute, Krembil Research Institute, University Health Network, Toronto Western Hospital, University of Toronto, Toronto, Ontario, Canada. Electronic address: nigil.haroon@uhn.ca.
¹³ Rheumatology Unit, Department of Precision Medicine, Università degli Studi della Campania "L. Vanvitelli", Naples, Italy. Electronic address: francesco.ciccia@unicampania.it.

PMID: 37075950
DOI: 10.1016/j.clim.2023.109332

Abstract

Ankylosing spondylitis (AS) is an inflammatory disease leading to spine ankylosis; however, the mechanisms behind new bone formation are still not fully understood. Single Nucleotide Polymorphisms (SNPs) in PTGER4, encoding for the receptor EP4 of prostaglandin E2 (PGE2), are associated with AS. Since the PGE2-EP4 axis participates in inflammation and bone metabolism, this work aims at investigating the influence of the prostaglandin-E2 axis on radiographic progression in AS. In 185 AS (97 progressors), baseline serum PGE2 predicted progression, and PTGER4 SNP rs6896969 was more frequent in progressors. Increased EP4/PTGER4 expression was observed in AS circulating immune cells, synovial tissue, and bone marrow. CD14highEP4 + cells frequency correlated with disease activity, and when monocytes were cocultured with mesenchymal stem cells, the PGE2/EP4 axis induced bone formation. In conclusion, the Prostaglandin E2 axis is involved in bone remodelling and may contribute to the radiographic progression in AS due to genetic and environmental upregulation.

Keywords: Ankylosing spondylitis; EP4; Monocytes; PTGER4; Prostaglandins; Radiographic progression.

MeSH terms

Dinoprostone*
Humans
Receptors, Prostaglandin E, EP4 Subtype / genetics
Receptors, Prostaglandin E, EP4 Subtype / metabolism
Spondylitis, Ankylosing* / diagnostic imaging
Spondylitis, Ankylosing* / genetics

Substances

Dinoprostone
Receptors, Prostaglandin E, EP4 Subtype