The polyadenylation inhibitor cordycepin reduces pain, inflammation and joint pathology in rodent models of osteoarthritis

Ashraf, Sadaf; Radhi, Masar; Gowler, Peter; Burston, James J.; Gandhi, Raj D.; Thorn, Graeme J.; Piccinini, Anna M.; Walsh, David A.; Chapman, Victoria; De Moor, Cornelia H.; Chapman, Victoria

Abstract

Clinically, osteoarthritis (OA) pain is significantly associated with synovial inflammation. Identification of the mechanisms driving inflammation could reveal new targets to relieve this prevalent pain state. Herein, a role of polyadenylation in OA synovial samples was investigated, and the potential of the polyadenylation inhibitor
cordycepin (3’ deoxyadenosine) to inhibit inflammation as well as to reduce pain and structural OA progression were studied.
Joint tissues from people with OA with high or low grade inflammation and non-arthritic post-mortem controls were analysed for the polyadenylation factor CPSF4 and inflammatory markers. Effects of cordycepin on pain behavior and joint pathology were studied in models of OA (intra-articular injection of monosodium iodoacetate in rats and surgical destabilisation of the medial meniscus in mice). Human monocyte-derived macrophages and a mouse macrophage cell line were used to determine effects of cordycepin on nuclear localisation of the inflammatory transcription factor NFĸB and polyadenylation factors (WDR33 and CPSF4).
CPSF4 and NFκB expression were increased in synovia from OA patients with high grade inflammation. Cordycepin reduced pain behaviour, synovial inflammation and joint pathology in both OA models. Stimulation of macrophages induced nuclear localisation of NFĸB and polyadenylation factors, effects inhibited by cordycepin. Knockdown of polyadenylation factors also prevented nuclear localisation of NFĸB.
The increased expression of polyadenylation factors in OA synovia indicates a new target for analgesia treatments. This is supported by the finding that polyadenylation factors are required for inflammation in macrophages and by the fact that the polyadenylation inhibitor cordycepin attenuates pain and pathology in models of OA.

Citation

Ashraf, S., Radhi, M., Gowler, P., Burston, J. J., Gandhi, R. D., Thorn, G. J., Piccinini, A. M., Walsh, D. A., Chapman, V., De Moor, C. H., & Chapman, V. (2019). The polyadenylation inhibitor cordycepin reduces pain, inflammation and joint pathology in rodent models of osteoarthritis. Scientific Reports, 9(1), 1-17. https://doi.org/10.1038/s41598-019-41140-1

• Journal Article Type: Article
• Acceptance Date: Feb 15, 2019
• Online Publication Date: Mar 18, 2019
• Publication Date: 2019-12
• Deposit Date: Feb 26, 2019
• Publicly Available Date: Mar 18, 2019
• Journal: Scientific Reports
• Electronic ISSN: 2045-2322
• Publisher: Nature Publishing Group
• Peer Reviewed: Peer Reviewed
• Volume: 9
• Issue: 1
• Article Number: 4696
• Pages: 1-17
• DOI: https://doi.org/10.1038/s41598-019-41140-1
• Keywords: Osteoarthritis; Pain; Inflammation; Polyadenylation; Cordycepin
• Public URL: https://nottingham-repository.worktribe.com/output/1585598
• Publisher URL: https://www.nature.com/articles/s41598-019-41140-1
• Additional Information: Received: 8 October 2018; Accepted: 15 February 2019; First Online: 18 March 2019; : The authors declare no competing interests.
• Contract Date: Mar 18, 2019