Britanin inhibits titanium wear particle-induced osteolysis and osteoclastogenesis

초록

Wear particle-induced osteolysis is a serious complication that occurs in individuals with titanium (Ti)-based implants following long-term usage due to loosening of the implants. The control of excessive osteoclast differentiation and inflammation is essential for protecting against wear particle-induced osteolysis. The present study evaluated the effect of britanin, a pseudoguaianolide sesquiterpene isolated from Inula japonica, on osteoclastogenesis in vitro and Ti particle-induced osteolysis in vivo. The effect of britanin was examined in the osteoclastogenesis of mouse bone marrow-derived macrophages (BMMs) using TRAP staining, RT-PCR, western blotting and immunocytochemistry. The protective effect of britanin was examined in a mouse calvarial osteolysis model and evaluated using micro-CT and histomorphometry. Britanin inhibited osteoclast differentiation and F-actin ring formation in the presence of macrophage colony-stimulating factor and receptor activator of nuclear factor kB ligand in BMMs. The expression of osteoclast-specific marker genes, including tartrate-resistant acid phosphatase, cathepsin K, dendritic cell-specific transmembrane protein, matrix metallopeptidase 9 and nuclear factor of activated T-cells cytoplasmic 1, in the BMMs was significantly reduced by britanin. In addition, britanin reduced the expression of B lymphocyte-induced maturation protein-1, which is a transcriptional repressor of negative osteoclastogenesis regulators, including interferon regulatory factor-8 and B-cell lymphoma 6. Conversely, britanin increased the expression levels of anti-oxidative stress genes, namely nuclear factor erythroid-2-related factor 2, NAD(P)H quinone oxidoreductase 1 and heme oxygenase 1 in the BMMs. Furthermore, the administration of britanin significantly reduced osteolysis in a Ti particle-induced calvarial osteolysis mouse model. Based on these findings, it is suggested that britanin may be a potential therapeutic agent for wear particle-induced osteolysis and osteoclast-associated disease.

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