DPHB inhibits osteoclastogenesis by suppressing NF-κB and MAPK signaling and alleviates inflammatory bone destruction.

Overactivation of osteoclasts disrupt the delicate balance between bone-resorbing osteoclasts and bone-forming osteoblasts, resulting in development of osteoporosis and various inflammatory disorders, including rheumatoid arthritis, spondyloarthropathies, and psoriatic arthritis. While inhibiting osteoclastogenesis represents a promising therapeutic strategy, current treatments targeting the RANKL pathway (such as bisphosphonates and denosumab) are associated with severe side effects, necessitating the development of safer alternatives. We hypothesize that the compound (4E)-7-(4-hydroxy-3-methoxyphenyl)-1-phenylhept-4-en-3-one (DPHB), derived from Alpinia officinarum Hance, can effectively inhibit RANKL-induced osteoclastic activity while maintaining a favorable safety profile. Through tartrate-resistant acid phosphatase (TRAP) staining and bone resorption pit assays, we demonstrate that DPHB inhibits osteoclast formation and function. Mechanistically, DPHB suppresses both NF-κB and MAPK signaling pathways while inhibiting NFATc1 activation and nuclear translocation, as evidenced by immunofluorescence staining, real-time PCR, and western blotting assays. In a LPS-induced inflammatory osteolysis mouse model, intraperitoneal administration of DPHB significantly alleviated bone destruction, confirmed through Micro-CT scanning, histological staining, and enzyme-linked immunosorbent assay (ELISA). Our findings establish DPHB as a promising osteoclast inhibitor for treating bone loss disorders through its dual suppression of osteoclastogenesis via NF-κB and MAPK signaling pathways and amelioration of inflammatory bone destruction.