Betulin inhibits titanium particle-induced osteolysis and attenuates RANKL-associated osteoclastogenesis by suppressing the MAPK pathway

Wear particle-induced aseptic loosening is an important factor compromising the long-term success of total joint replacement. It is often associated with osteolysis and inflammatory cellular responses within the joint. Betulin, a pentacyclic triterpenoid, promotes osteoblast differentiation and suppresses osteoclast formation. This study aimed to explore the therapeutic effect of betulin on aseptic loosening induced by wear particles and its underlying mechanism. A mouse calvarial model was used to study the effects of betulin on titanium particle-induced osteolysis in vivo. RAW264.7 murine macrophages were used to analyze titanium particle-induced inflammation and receptor activator of nuclear factor-κB ligand (RANKL)-induced osteoclastogenesis in vitro. In mice with calvarial osteolysis induced by titanium particles, betulin treatment reduced the resorption pits and inhibited the expression of osteoclast-specific genes and inflammation-related genes. In RAW264.7 murine macrophages, betulin treatment inhibited the inflammatory response induced by particles and reduced RANKL-associated osteoclastogenesis by suppressing the mitogen-activated protein kinase (MAPK) pathway. These results indicate that betulin can inhibit titanium particle-induced osteolysis, an ability that is likely associated with reduced particle-induced inflammation and osteoclast activation. Based on these findings, betulin is proposed as a potential therapeutic candidate to mitigate wear particle-induced aseptic loosening.