A formyl peptide receptor agonist suppresses inflammation and bone damage in arthritis.
OBJECTIVE
Annexin A1 (AnxA1) 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).


METHODS
Arthritis was induced by injection of K/BxN serum at day 0 and 2 in wild-type (WT) or AnxA1(-/-) mice and clinical and histopathological manifestations measured 8-11 days later. WT mice were given the FPR agonist compound 43 (Cpd43) (6 or 30 mg·kg(-1) i.p.) for 4 days. Effects of AnxA1 and Cpd43 on RANKL-induced osteoclastogenesis were assessed in RAW 264.7 cells and human RA FLS and macrophages.


RESULTS
Treatment with Cpd43 before or after the onset of arthritis reduced clinical disease severity and attenuated synovial TNF-α and osteoclast-associated gene expression. Deletion 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 inhibited IL-6 release, while blocking FPR2 or silencing AnxA1 increased this release.


CONCLUSIONS
The FPR agonist Cpd43 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.
Centre for Inflammatory Diseases, Faculty of Medicine, Nursing and Health Sciences, Monash Medical Centre, Monash University, Clayton, Vic., Australia; Department of Microbiology, Harbin Medical University, Harbin, China.
W
W
Kao
R
R
Gu
Y
Y
Jia
Xuemin
X
Wei
H
H
Fan
J
J
Harris
Zhiyi
Z
Zhang
J
J
Quinn
E F
EF
Morand
Y H
YH
Yang
D000818:Animals; D017305:Annexin A1 / Q000172:deficiency / Q000378:metabolism; D001169:Arthritis, Experimental / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D001172:Arthritis, Rheumatoid / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology*; D001842:Bone and Bones / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D002478:Cells, Cultured; D004195:Disease Models, Animal; D007249:Inflammation / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010671:Phenylurea Compounds / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D011720:Pyrazoles / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D044042:Receptors, Formyl Peptide / Q000819:agonists* / Q000378:metabolism; D013329:Structure-Activity Relationship
D017305:Annexin A1; D010671:Phenylurea Compounds; D011720:Pyrazoles; D044042:Receptors, Formyl Peptide; C481578:formyl peptide receptor 2, mouse