| First Author | Yoshida S | Year | 2024 |
| Journal | J Bone Miner Res | Volume | 39 |
| Issue | 3 | Pages | 341-356 |
| PubMed ID | 38477771 | Mgi Jnum | J:360484 |
| Mgi Id | MGI:7797629 | Doi | 10.1093/jbmr/zjae015 |
| Citation | Yoshida S, et al. (2024) Bub1 suppresses inflammatory arthritis-associated bone loss in mice through inhibition of TNFalpha-mediated osteoclastogenesis. J Bone Miner Res 39(3):341-356 |
| abstractText | 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 (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 (Bub1DeltaLysM) mice were generated. Bub1DeltaLysM 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 Bub1DeltaLysM 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 Bub1DeltaLysM mice. Indeed, osteoclastogenesis using BMMs derived from Bub1DeltaLysM was enhanced by RANKL and tumor necrosis factor-alpha or RANKL and IL-1beta 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. |
