Non-covalent proteasome inhibitor PI1840 suppresses osteoclastogenesis and prevents LPS-induced osteolysis in mice.

Excessive osteoclast-mediated bone resorption is a hallmark of osteolytic disorders, including aseptic prosthetic loosening, osteoporosis, and rheumatoid arthritis. Therefore, the identification of agents that effectively suppress osteoclast differentiation and function is critical for the prevention and treatment of pathological bone loss. PI1840, a non-covalent proteasome inhibitor, has been reported to inhibit the proliferation of multiple tumor cell lines; however, its role in osteoclast-associated bone diseases remains unclear. Here, we demonstrate for the first time that PI1840 markedly suppresses RANKL-induced osteoclastogenesis and bone-resorptive activity by downregulating the master transcription factor NFATc1 and its upstream regulator c-Fos through inhibition of the NF-κB and MAPK (p38 and JNK) signaling pathways. Moreover, in a murine model of lipopolysaccharide-induced calvarial osteolysis, PI1840 administration significantly alleviated bone destruction, as evidenced by micro-computed tomography and histological analyses. Collectively, these findings identify PI1840 as a promising therapeutic candidate for osteolytic diseases driven by aberrant osteoclast activation.