| Budget Amount *help |
¥3,890,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥390,000)
Fiscal Year 2007: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
Fiscal Year 2006: ¥2,200,000 (Direct Cost: ¥2,200,000)
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| Research Abstract |
Rheumatoid arthritis (RA) is characterized by histopathologic features, including synovial proliferation, inflammatory cell infiltration, neovascularization, and osteoclast formation at the synovial membrane. Synovial macrophages are potentially originated from monocytes in circulation. Moreover, recent studies indicate capacity of circulating monocytes to differentiate into osteoclasts, endothelial cells, and pericytes. Therefore, bone marrow (BM)-derived monocytes may contribute to RA pathogenesis by homing to the joint and differentiating into synovial macrophages, osteoclasts, endothelial cells, and pericytes. In this study, our hypothesis was examined using a mouse model for RA-like arthritis.
1. Examination of a role for BM-derived cells in the mouse model of arthritis
We successfully generated BM chimera mice, in which > 95% of CD45^+ cells in circulation, spleen, and BM expressed GFP. Repeated injections of K/BxN serum to mice induced chronic destructive arthritis with pannus for
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mation and bone erosion. The study using immunostaining revealed that > 90% of osteoclasts, half of synovial macrophages, and a part of pericytes were GFP^+ BM-derived cells in the affected joints, but none of endothelial cells expressed GFP.
2. Examination of a role for BM-derived monocyte lineage cells in the mouse model of arthritis using recombinant adenovirus expressing soluble macrophage-colony stimulating factor receptor (sM-CSFR)
To neutralize endogenous M-CSF essential to the development of monocyte-lineage cells, mice were pretreated with intravenous injection of recombinant adenovirus expressing sM-CSFR (Ad-sM-CSFR) or control virus lacking M-CSF binding domain one and four weeks before administration of K/BxN serum. Adenovirus expressing interleukin-1 receptor antagonist (Ad-IL-1R_a) was also used as a control. Preteatment with Ad-sM-CSFR prevented development of destructive arthritis, as that with Ad-IL-1R_a did. In contract, pretreatment with control virus did not.
These findings together indicate that BM-derived monocytes contribute to development of mouse model for RA-like arthritis by homing to the joint and differentiating into synovial macrophages, osteoclasts, and pericytes. Less
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