Inhibition of NF-κB and ERK Signaling by Pristimerin Mitigates Osteoclast Formation and OVX-Induced Bone Loss

Osteoporosis is a bone disorder marked by reduced bone density and increased fracture risk, primarily due to enhanced formation or activity of bone-resorbing osteoclasts. Although current anti-resorptive therapies can effectively reduce osteoclast-mediated bone loss, their long-term use is often limited by adverse effects. Pristimerin (PRI), a naturally occurring quinone-methide triterpenoid, has been reported to possess anti-inflammatory and anti-cancer properties through modulation of signaling pathways, including NF-κB and MAPK. The anti-osteoclastic and bone-resorptive effects of PRI were examined in vitro using bone marrow-derived macrophages. Additionally, an ovariectomized (OVX) mouse model was employed to evaluate the protective effects of PRI against bone loss in vivo. PRI inhibited early activation of NF-κB and ERK MAPK signaling, thereby suppressing downstream targets c-Fos and NFATc1 and preventing osteoclast maturation. In the OVX model, PRI effectively mitigated bone loss by reducing osteoclast formation and resorptive activity. These findings suggest that PRI holds promise as a therapeutic agent for osteoclast-driven bone diseases such as osteoporosis by targeting key signaling pathways involved in osteoclast differentiation and function.