RESEARCH - The pathogenic role of CXCR7 in RA

[Guest guest]

Arthritis Rheum. 2010 Jul 8. [Epub ahead of print]

Pathogenic role of CXCR7 in rheumatoid arthritis.

Watanabe K, Penfold ME, Matsuda A, Ohyanagi N, Kaneko K, Miyabe Y,

Matsumoto K, Schall TJ, Miyasaka N, Nanki T.

Tokyo Medical and Dental University, Tokyo, Japan.

Abstract

OBJECTIVE.: The interaction between CXCL12 and its receptor, CXCR4, in

the synovium of rheumatoid arthritis (RA) patients is important for

local inflammatory cell recruitment, angiogenesis, and cytokine

production. CXCR7 was recently identified as an alternative receptor

for CXCL12. This study analyzed the expression of CXCR7 in the RA

synovium and the pathogenic role of the CXCL12/CXCR7 pathway in RA.

METHODS.: CXCR7 expression in synovial tissue of RA was analyzed by

immunohistochemistry, while expression of CXCR4 and CXCR7 in human

umbilical vein endothelial cells (HUVECs) was examined by quantitative

RT-PCR and flow cytometry. Tube-formation and rat aortic ring

angiogenesis assays assessed the effects of CXCR7 antagonist, CCX733,

CXCR4 antagonist, AMD3100 and anti-CXCR4 mAb on CXCL12-incued

angiogenesis. The effects of CCX733 in a murine collagen-induced

arthritis (CIA) model were also evaluated.

RESULTS.: CXCR7 was expressed on endothelial cells in the RA synovium

and also on unstimulated HUVECs. The expression of CXCR7 on HUVECs was

markedly upregulated by IL-1beta stimulation, and this overexpression

was further enhanced by CXCL12 treatment. Incubation with CXCL12 also

promoted angiogenic activity, with addition of IL-1beta again

augmenting the effect. The CXCL12-induced angiogenesis was inhibited

by both CXCR4 and CXCR7 antagonists and anti-CXCR4 mAb. Furthermore,

treatment with CCX733 significantly reduced clinical arthritis scores

and number of vessels in the inflamed synovial tissue in CIA mice.

CONCLUSION.: CXCR7 and CXCR4 are both important for angiogenesis in

the RA synovium, making CXCR7 another potential target molecule for

novel RA angiogenesis-blocking therapies.

PMID: 20617529

http://www.ncbi.nlm.nih.gov/pubmed/20617529

Not an MD