Budding uninhibited by benzimidazoles 1 () is highly expressed in synovium from rheumatoid arthritis patients and associated with bone loss.
Bub1 was found to be highly expressed in the synovium of RA patients and in murine models of arthritis.
Myeloid cells in mice were identified as a significant population expressing Bub1.
Mice with a specific deletion of Bub1 in myeloid cells showed reduced femoral bone mineral density without significant differences in joint inflammation or bone erosion.
Increased bone resorption due to enhanced osteoclast activity was observed in Bub1-deleted mice during arthritis.
The nuclear factor-kappa B pathway was significantly enriched in bone marrow-derived macrophages from Bub1-deleted mice following stimulation.
Bub1 appears to inhibit inflammation-mediated , suggesting a protective role against bone loss in inflammatory arthritis.
Simplified
Rheumatoid arthritis (RA) is an inflammatory autoimmune disease characterized by synovitis, bone and cartilage destruction, and increased fracture risk with bone loss. Although disease-modifying antirheumatic drugs have dramatically improved clinical outcomes, these therapies are not universally effective in all patients because of 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 () 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 when compared with control (Ctrl) mice under K/BxN serum-transfer arthritis, 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 demonstrated a significantly enriched nuclear factor-kappa B pathway among upregulated genes in receptor activator of nuclear factor kappa B ligand (RANKL)-stimulated bone marrow-derived macrophages (BMMs) obtained from Bub1ΔLysM mice. Indeed, using BMMs derived from Bub1ΔLysM was enhanced by RANKL and tumor necrosis factor-α or RANKL and IL-1β treatment compared with Ctrl. 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.
Key numbers
significantly lower in ΔLysM compared with Ctrl
Decrease in Bone Mineral Density
Femoral bone mineral density measured under K/BxN serum-transfer arthritis.
higher in ΔLysM-derived BMMs
Increased
Osteoclast formation induced by TNFα and RANKL treatment.
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