A novel benzamide derivative protects ligature-induced alveolar bone erosion by inhibiting NFATc1-mediated osteoclastogenesis

• Published in: Toxicology and applied pharmacology 2018-09, Vol.355, p.9-17
• Main Authors: Ihn, Hye Jung, Lee, Taeho, Lee, Doohyun, Kim, Ju Ang, Kim, Kiryeong, Lim, Soomin, Kim, Jae-Young, Lee, Youngkyun, Kim, Sang-Hyun, Lee, Hyun-Shik, Shin, Hong-In, Park, Eui Kyun
• Format: Article
• Language: English
• Subjects: Actins - biosynthesis; Alveolar bone loss; Alveolar Bone Loss - prevention & control; Animals; Benzamide; Benzamides - pharmacology; Bone resorption; Cell Differentiation - drug effects; Ligation; Male; MAP Kinase Signaling System - drug effects; Mice; Mice, Inbred C57BL; NF-kappa B - drug effects; NFATC Transcription Factors - antagonists & inhibitors; OCLI-070; Osteoclast; Osteoclasts - drug effects; Osteogenesis - drug effects; Periodontitis - prevention & control; Protective Agents - pharmacology; RANK Ligand - biosynthesis
• ISSN: 0041-008X; 1096-0333
• DOI: 10.1016/j.taap.2018.06.017

Since elevated osteoclast formation and/or activity by inhibitory responses against pathogens leads to diverse osteolytic bone diseases including periodontitis, inhibition of osteoclast differentiation and bone resorption has been a primary therapeutic strategy. In this study, we investigated the therapeutic potential of a novel benzamide-linked molecule, OCLI-070, for preventing alveolar bone loss in mice with ligature-induced experimental periodontitis. OCLI-070 inhibited osteoclast formation by acting on both early and late stages of differentiation, and attenuated the induction of nuclear factor of activated T-cells, cytoplasmic 1 (NFATc1) and the expression of osteoclast-specific genes. In addition, OCLI-070 significantly suppressed the formation of actin rings and resorption pits. Analysis of the inhibitory action of OCLI-070 showed that it markedly suppressed receptor activator of nuclear factor-κB ligand (RANKL)-induced extracellular signal-regulated kinase (ERK) and NF-κB signaling cascades. Moreover, OCLI-070 prevented ligature-induced alveolar bone erosion in mice by suppressing osteoclast formation. These findings demonstrate that OCLI-070 attenuated osteoclast differentiation and function as well as ligature-induced bone erosion by inhibiting RANKL-mediated ERK and NF-κB signaling pathways. •OCLI-070 inhibits osteoclast differentiation from bone marrow-derived macrophages.•OCLI-070 significantly attenuates the bone-resorbing activity.•OCLI-070 suppresses RANKL-induced MEK-ERK and NF-κB pathways.•OCLI-070 protects ligature-induced alveolar bone loss.