A formyl peptide receptor agonist suppresses inflammation and bone damage in arthritis

Wenping Kao, Ran Gu, Yuan Jia, Xuemin Wei, Huapeng Fan, James Harris, Zhiyi Zhang, Julian Michael Warner Quinn, Eric Francis Morand, Yuan Hang Yang

Research output: Contribution to journalArticleResearchpeer-review

27 Citations (Scopus)

Abstract

BACKGROUND AND PURPOSE: Annexin A1 (AnxA1) is an endogenous anti-inflammatory molecule that binds to the formyl-peptide receptor 2 (FPR2). However, the potential for therapeutic FPR ligands to modify immune-mediated disease has been little explored. We investigated the effects of a synthetic FPR ligand on joint disease in the K/BxN model of RA and RA fibroblast-like synoviocytes (FLS). EXPERIMENTAL APPROACH: Arthritis was induced by injection of K/BxN serum at day 0 and 2 in wild-type or AnxA1-/- mice, and clinical and histopathologic manifestations measured. WT mice were treated with the FPR agonist compound 43 (Cpd43) (6 or 30 mg/kg). Effects of AnxA1 and Cpd43 were also assessed in RANKL- induced osteoclastogenesis in RAW 264.7 cells, and in human RA FLS and macrophages. KEY RESULTS: Treatment with Cpd43 before or after the onset of arthritis significantly reduced clinical disease severity and attenuated synovial TNF-alpha and osteoclast-associated gene expression. Conversely, deficiency of AnxA1 in mice exacerbated arthritis severity in the K/BxN model. In vitro, Cpd43 suppressed osteoclastogenesis and NFAT activity elicited by RANKL, and inhibited IL-6 secretion by mouse macrophages. In human RA joint-derived FLS and monocyte-derived macrophages, Cpd43 treatment also inhibited IL-6 release, while blocking FPR2 or silencing AnxA1 had the reverse effect. CONCLUSIONS AND IMPLICATIONS: These data demonstrate that the FPR agonist Cpd43 reduces osteoclastogenesis and inflammation in a mouse model of RA and exhibited anti-inflammatory effects in relevant human cells. These data suggest that FPR ligands may represent novel therapeutic agents with which to ameliorate inflammation and bone damage in RA.
Original languageEnglish
Pages (from-to)4087-4096
Number of pages10
JournalBritish Journal of Pharmacology
Volume171
Issue number17
DOIs
Publication statusPublished - Sep 2014

Cite this