Britanin inhibits titanium wear particle­induced osteolysis and osteoclastogenesis.

ABSTRACT

Wear particle­induced osteolysis is a serious complication that occurs in individuals with titanium (Ti)­based implants following long­term usage due to loosening of the implants. The control of excessive osteoclast differentiation and inflammation is essential for protecting against wear particle­induced osteolysis. The present study evaluated the effect of britanin, a pseudoguaianolide sesquiterpene isolated from Inula japonica, on osteoclastogenesis in vitro and Ti particle­induced osteolysis in vivo. The effect of britanin was examined in the osteoclastogenesis of mouse bone marrow­derived macrophages (BMMs) using TRAP staining, RT­PCR, western blotting and immunocytochemistry. The protective effect of britanin was examined in a mouse calvarial osteolysis model and evaluated using micro­CT and histomorphometry. Britanin inhibited osteoclast differentiation and F­actin ring formation in the presence of macrophage colony­stimulating factor and receptor activator of nuclear factor kB ligand in BMMs. The expression of osteoclast­specific marker genes, including tartrate­resistant acid phosphatase, cathepsin K, dendritic cell­specific transmembrane protein, matrix metallopeptidase 9 and nuclear factor of activated T­cells cytoplasmic 1, in the BMMs was significantly reduced by britanin. In addition, britanin reduced the expression of B lymphocyte­induced maturation protein­1, which is a transcriptional repressor of negative osteoclastogenesis regulators, including interferon regulatory factor­8 and B­cell lymphoma 6. Conversely, britanin increased the expression levels of anti­oxidative stress genes, namely nuclear factor erythroid­2­related 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 particle­induced calvarial osteolysis mouse model. Based on these findings, it is suggested that britanin may be a potential therapeutic agent for wear particle­induced osteolysis and osteoclast­associated disease.