Abstract
Inflammatory osteolysis is a common osteolytic specificity that occurs during infectious orthopaedic surgery and is characterized by an imbalance in bone homeostasis due to excessive osteoclast bone resorption activity. Epothilone B (Epo B) induced α-tubulin polymerization and enhanced microtubule stability, which also played an essential role in anti-inflammatory effect on the regulation of many diseases. However, its effects on skeletal system have rarely been investigated. Our study demonstrated that Epo B inhibited osteoclastogenesis in vitro and prevented inflammatory osteolysis in vivo. Further analysis showed that Epo B also markedly induced mature osteoclasts apoptosis during osteoclastogenesis. Mechanistically, Epo B directly suppressed osteoclastogenesis by the inhibitory regulation of the phosphorylation and activation of PI3K/Akt/STAT3 signaling directly, and the suppressive regulation of the CD9/gp130/STAT3 signaling pathway indirectly. The negative regulatory effect on STAT3 signaling further restrained the translocation of NF-κB p65 and NFATc1 from the cytosol to the nuclei during RANKL stimulation. Additionally, the expression of osteoclast specific genes was also significantly attenuated during osteoclast fusion and differentiation. Taken together, these findings illustrated that Epo B protected against LPS-induced bone destruction through inhibiting osteoclastogenesis via regulating the STAT3 dependent signaling pathway.
Highlights
Decreased bone mineral metabolic activity was an essential aging associated characteristic
The binding of RANKL to RANK triggered the activation of nuclear factor-kappa B (NF-κB), mitogen-activated protein kinases (MAPKs), signal transducer and activator of transcription 3 (STAT3) and other classical signaling pathways to induce osteoclastogenesis [6]. c-Fos acted as an essential transcription factor that initialed the expression of the nuclear factor of activated T-cells cytoplasmic1 (NFATc1) during osteoclast differentiation, proliferation and maturation [7]
Since Epothilone B (Epo B) showed no significant difference in cytotoxicity analysis and cell cycle, we further detected the cell apoptosis at the same concentration of Epo B during osteoclastogenesis
Summary
Decreased bone mineral metabolic activity was an essential aging associated characteristic. Infectious bone diseases including osteomyelitis, orthopaedic implantassociated infection and other severe inflammatory osteolysis destroyed dynamic bone matrix homeostasis (regulated by osteoclast-mediated bone resorption and osteoblast-mediated bone formation) [1,2,3]. Osteoclasts were derived from haematopoietic stem cells (HSCs), which were differentiated by macrophage colony stimulating factor (M-CSF) and receptor activator of NFκB ligand (RANKL) [5]. Monocyte/macrophage lineage cell-cell fusion was another unique process in osteoclastogenesis. During this process, CD9 played an essential role in regulating membrane fusion and the formation of multinucleated cells. In several inflammatory osteolysis diseases, excessive osteoclast fusion and bone resorption activity were considered as significant elements to result in bone loss
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