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CP-25 reverses prostaglandin E4 receptor desensitizationinduced fibroblast-like synoviocyte dysfunction via the G protein-coupled receptor kinase 2 in autoimmune arthritis

Authors: Xiao-yi Jia1,2, Yan Chang1, Fang Wei1, Xing Dai1, Yu-jing Wu1, Xiao-jing Sun1, Shu Xu1, Hua-xun Wu1, Chun Wang1, Xue-zhi Yang1, Wei Wei1
1 Institute of Clinical Pharmacology, Anhui Medical University, Key Laboratory of Anti-inflammatory and Immune Medicine, Ministry of Education, Anhui Collaborative Innovation Center of Anti-inflammatory and Immune Medicine, Hefei 230032, China
2 School of Pharmacy, Anhui University of Chinese Medicine, Hefei 230038, China
Correspondence to: Wei Wei: wwei@ahmu.edu.cn,
DOI: 10.1038/s41401-018-0196-2
Received: 12 July 2018
Accepted: 13 November 2018
Advance online: 14 January 2019

Abstract

Paeoniflorin-6’-O-benzene sulfonate (CP-25) is a novel compound derived from paeoniflorin that has been demonstrated to have therapeutic effects in a rat model of rheumatoid arthritis (RA). However, the underlying mechanism has not been elucidated to date. We explored this mechanism in the present study by treating rats with adjuvant arthritis (AA) with CP-25. We found that the membrane EP4 protein level was downregulated; whereas, GRK2 was upregulated, in fibroblast-like synoviocyte (FLS)s of AA rats. Prostaglandin (PGE)2 stimulated FLS proliferation and enhanced the membrane EP4 receptor protein level; the latter was reversed by the administration of an EP4 receptor agonist, whereas the membrane GRK2 protein level gradually increased. The changes in the EP4 receptor and GRK2 expression were enhanced by TNF-α, and the former was accompanied by an alteration in the cyclic (c) AMP level. The EP4 receptor agonist stimulation increased the association between GRK2 and the EP4 receptor. GRK2 knockdown abrogated the abnormalities in FLS proliferation. The CP-25 treatment (100 mg/kg) suppressed joint inflammation with an efficacy that was similar to that of methotrexate. This finding was associated with EP4 upregulation and GRK2 downregulation in FLSs. Thus, GRK2 plays an important role in the abnormal FLS proliferation observed in AA possibly by promoting EP4 receptor desensitization and decreasing the cAMP level. Our results demonstrate that CP-25 has therapeutic potential for the treatment of human RA via GRK2 regulation.
Keywords: adjuvant-induced arthritis; paeoniflorin-6’-O-benzene sulfonate; fibroblast-like synoviocytes; G protein-coupled receptor kinase 2; prostaglandin E2

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