Summary

Wear particle-induced periprosthetic osteolysis is a common complication after total joint arthroplasty. Osteoclast is one of key therapeutic targets to control the pathological process, which can be inhibited with ursolic acid.

Abstract

Purpose

The excessive activation of osteoclasts plays a pivotal role in periprosthetic loosening resulting from wear particle-induced osteolysis, and medicine prevention is a feasible therapeutic method. 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 wear particle-induced osteolysis requires further investigation. In this study, we evaluated the effects of UA on osteoclastogenesis and wear particle-induced osteolysis in vitro and in vivo, and explored its possible mechanism of action.

Methods

The inducing culture of osteoclast-like cells in vitro and titanium (Ti) particle-induced mouse calvarial osteolysis model were performed. Tartrate-resistant acid phosphatase (TRAP), qPCR, western blot, immunofluorescence staining, micro-CT and histological staining etc. were used to elucidate effects of UA on osteoclasts and mechanism of action.

Results

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 Ti particle-induced mouse calvarial bone loss, and decreased the number of TRAP-positive osteoclasts.

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.