愛媛大学プロテオサイエンスセンター病態生理解析部門・教授今井 祐記Yuuki ImaiDivision of Integrative Pathophysiology, Proteo-Science Center, Ehime UniversityAbstractRheumatoid arthritis (RA) is an inflammatory autoimmune disease characterized by synovitis, bone and cartilage destruction, and increased fracture risk with bone loss. Although disease-modifying anti-rheumatic drugs (DMARDs) have dramatically improved clinical outcomes, these therapies are not universally effective in all patients due to the heterogeneity of RA pathogenesis. Therefore, it is necessary to elucidate the molecular mechanisms underlying RA pathogenesis, including associated bone loss, in order to identify novel therapeutic targets. In this study, we found that Budding uninhibited by benzimidazoles 1 (BUB1) was highly expressed in RA patients’ synovium and murine ankle tissue with arthritis. As CD45+CD11b+ myeloid cells are a Bub1 highly expressing population among synovial cells in mice, myeloid cell-specific Bub1 conditional knockout (Bub1ΔLysM) mice were generated. Bub1ΔLysM mice exhibited reduced femoral bone mineral density (BMD) when compared to control mice under K/BxN serum-transfer arthritis (STA), with no significant differences in joint inflammation or bone erosion based on a semi-quantitative erosion score and histological analysis. Bone histomorphometry revealed that femoral bone mass of Bub1ΔLysM under arthritis was reduced by increased osteoclastic bone resorption. RNA-seq and subsequent Gene Set Enrichment Analysis (GSEA) demonstrated a significantly enriched NF-κB pathway among up-regulated genes in RANKL-stimulated bone marrow-derived macrophages (BMMs) obtained from Bub1ΔLysM mice. Indeed, osteoclastogenesis using BMMs derived from Bub1ΔLysM was enhanced by RANKL and TNFα or RANKL and IL-1β treatment compared to controls. Finally, osteoclastogenesis was increased by Bub1 inhibitor BAY1816032 treatment in BMMs derived from wildtype mice. These data suggest that Bub1 expressed in macrophages plays a protective role against inflammatory arthritis-associated bone loss through inhibition of inflammation-mediated osteoclastogenesis.― 35 ―ゲノムワイド解析を駆使した関節リウマチ新規治療標的の探索Exploring…novel…therapeutic…targets…for…rheumatoid…arthritisusing…genome-wide…analysis
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