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Excessive osteoclastic activity results in pathological bone resorptive diseases, such as osteoporosis, periodontitis, and rheumatoid arthritis. As imidazole-containing compounds possess extensive therapeutic potential for the management of diverse diseases, we synthesized a series of imidazole derivatives and investigated their effects on osteoclast differentiation and function. In the present study, we found that a novel imidazole derivative, KP-A038, suppressed receptor activator of nuclear factor-κB ligand (RANKL)-mediated osteoclastogenesis and bone-resorbing activity  in vitro  and attenuated lipopolysaccharide (LPS)-induced bone destruction  in vivo . KP-A038 significantly inhibited the induction of nuclear factor of activated T-cells, cytoplasmic 1 (NFATc1) and the expression of its target genes, including tartrate-resistant acid phosphatase ( Acp5 ), cathepsin K ( Ctsk ), dendritic cell-specific transmembrane protein ( Dcstamp ), and matrix metallopeptidase 9 ( Mmp9 ). KP-A038 upregulated the expression of negative regulators of osteoclast differentiation, such as interferon regulatory factor-8 ( Irf8 ) and B-cell lymphoma 6 ( Bcl6 ). Consistently, KP-A038 downregulated the expression of B lymphocyte-induced maturation protein-1 (Blimp1 encoded by  Prdm1 ), a repressor for  Irf8  and  Bcl6 . Moreover, administration of KP-A038 reduced LPS-induced bone erosion by suppressing osteoclast formation  in vivo . Thus, our findings suggest that KP-A038 may serve as an effective therapeutic agent for the treatment and/or prevention of bone loss in pathological bone diseases, including osteoporosis and periodontitis.

Inhibitory Effect of KP-A038 on Osteoclastogenesis and Inflammatory Bone Loss Is Associated With Downregulation of Blimp1