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A formyl peptide receptor agonist suppresses inflammation and bone damage in arthritis
Author(s) -
Kao W,
Gu R,
Jia Y,
Wei Xuemin,
Fan H,
Harris J,
Zhang Zhiyi,
Quinn J,
Morand E F,
Yang Y H
Publication year - 2014
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/bph.12768
Subject(s) - agonist , arthritis , inflammation , rankl , chemistry , medicine , endocrinology , formyl peptide receptor , synovitis , receptor , inflammatory arthritis , osteoclast , pharmacology , rheumatoid arthritis , immunology , activator (genetics) , chemotaxis
Background and Purpose Annexin A 1 ( A nx A 1) is an endogenous anti‐inflammatory protein and agonist of 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 agonist on joint disease in the K / BxN model of rheumatoid arthritis ( 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 ( WT ) or A nx A 1 −/− mice and clinical and histopathological manifestations measured 8–11 days later. WT mice were given the FPR agonist compound 43 ( C pd43) (6 or 30 mg·kg −1 i.p.) for 4 days. Effects of A nx A 1 and C pd43 on RANKL ‐induced osteoclastogenesis were assessed in RAW 264.7 cells and human RA FLS and macrophages. Key Results Treatment with C pd43 before or after the onset of arthritis reduced clinical disease severity and attenuated synovial TNF ‐α and osteoclast‐associated gene expression. Deletion of A nx A 1 in mice exacerbated arthritis severity in the K / BxN model. In vitro , C pd43 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, C pd43 treatment inhibited IL ‐6 release, while blocking FPR2 or silencing A nx A 1 increased this release. Conclusions and Implications The FPR agonist C pd43 reduced 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 capable of ameliorating inflammation and bone damage in RA .