Inhibitory effects of ursolic acid on osteoclastogenesis and titanium particle-induced osteolysis are mediated primarily via suppression of NF-κB signaling

Abstract

Ursolic acid (UA), a pentacyclic triterpenoid found in a variety of plants, has attracted considerable attention because of its important biological and pharmacological activities. However, its effect on osteoclasts and mechanism of action require further investigation. In this study, we evaluated the effects of UA on osteoclastogenesis and osteoclast-mediated osteolysis in vitro and in vivo, and explored its possible mechanism of action. The results indicated that UA could inhibit receptor activator of nuclear factor-κB ligand (RANKL)-mediated osteoclastogenesis and the bone resorptive function of osteoclasts in a concentration-dependent manner in vitro. Further, UA effectively inhibited the mRNA and protein expression of NFATc1, primarily via the suppression of nuclear factor-κB (NF-κB) signaling, and partly through the suppression of c-Jun N-terminal kinase (JNK) signaling. Additionally, UA treatment downregulated the expression of NFATc1-regulated osteoclast marker genes. Likewise, UA induced dose-dependent attenuation of titanium (Ti) particle-induced mouse calvarial bone loss, and decreased the number of tartrate-resistant acid phosphatase (TRAP)-positive osteoclasts. In conclusion, these results demonstrate that UA protects against wear particle-induced osteolysis by suppressing osteoclast formation and function. These effects are associated with the inhibition of the NF-κB- and JNK-related signaling pathways.

Keywords: NF-κB; Osteoclastogenesis; Osteolysis; Titanium particle; Ursolic acid.