AUTHOR=Ihn Hye Jung , Lee Taeho , Lee Doohyun , Bae Jong-Sup , Kim Sang-Hyun , Jang Il Ho , Bae Yong Chul , Shin Hong-In , Park Eui Kyun 

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

JOURNAL=Frontiers in Pharmacology

VOLUME=10

YEAR=2019

URL=https://www.frontiersin.org/journals/pharmacology/articles/10.3389/fphar.2019.00367

DOI=10.3389/fphar.2019.00367

ISSN=1663-9812

ABSTRACT=<p>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 <italic>in vitro</italic> and attenuated lipopolysaccharide (LPS)-induced bone destruction <italic>in vivo</italic>. 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 (<italic>Acp5</italic>), cathepsin K (<italic>Ctsk</italic>), dendritic cell-specific transmembrane protein (<italic>Dcstamp</italic>), and matrix metallopeptidase 9 (<italic>Mmp9</italic>). KP-A038 upregulated the expression of negative regulators of osteoclast differentiation, such as interferon regulatory factor-8 (<italic>Irf8</italic>) and B-cell lymphoma 6 (<italic>Bcl6</italic>). Consistently, KP-A038 downregulated the expression of B lymphocyte-induced maturation protein-1 (Blimp1 encoded by <italic>Prdm1</italic>), a repressor for <italic>Irf8</italic> and <italic>Bcl6</italic>. Moreover, administration of KP-A038 reduced LPS-induced bone erosion by suppressing osteoclast formation <italic>in vivo</italic>. 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.</p>