A structural modulator of tumor necrosis factor type 1 receptor promotes bone formation under lipopolysaccharide-induced inflammation in a murine tooth extraction model

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• 作者：Hiroyuki Nakachi^a ; ^b ; Kazuhiro Aoki^b ; ^{kazu.hpha@tmd.ac.jp} ; Nobuyoshi Tomomatsu^a ; ^b ; Neil Alles^b ; ^c ; Kenichi Nagano^b ; Masashi Yamashiro^a ; Hongtao Zhang^d ; Ramachandran Murali^d ; ^e ; Mark I. Greene^d ; Keiichi Ohya^b ; Teruo Amagasa^a
• 关键词：TNF-伪 antagonist ; Tooth extraction model ; Bone formation ; Inflammation ; Bone destruction
• 刊名：European Journal of Pharmacology
• 出版年：2012
• 期刊代码：24_00142999
• 类别：neu
• 出版时间：15 March, 2012
• 卷：679
• 期：1-3
• 页码：132-138
• 文件大小：754 K

摘要

Recently an increase in the serum levels of a bone formation marker after anti-tumor necrosis factor (TNF)-伪 therapy in rheumatoid arthritis patients has been reported. However, there remains no direct evidence that TNF-伪 antagonist could accelerate bone formation under inflammatory condition. Cavity-induced allosteric modification (CIAM) compound, F002, is a newly developed-TNF-伪 antagonist, which was designed by using the structure of TNF type 1 receptor, thus preventing TNF-伪-induced signaling. In this study, we examined whether the CIAM compound can promote bone formation under inflammatory condition induced by lipopolysaccharide (LPS). Thirty-six 10-week-old male mice (C57BL/6J) were used. Half of the mice received 10 mg/kg LPS, while the other half received PBS. Thereafter, incisor extraction was performed at 4 days after either LPS or PBS injection. Intraperitoneal injections of 2 mg/kg/day, 4 mg/kg/day CIAM, or vehicle (10%DMSO) were performed once a day from day 0 to day 7 after incisor tooth extraction. The mice were sacrificed at 21 days after the extraction. The regenerated bone mineral density (BMD) in the tooth socket, and the mineral apposition rate and the bone formation rate, direct evidences of bone formation, were significantly decreased in the LPS-injected group compared to the PBS-injected group. CIAM compound dose-dependently prevented the decrease of BMD under the LPS-injected condition, and promoted both the mineral apposition rate and the bone formation rate significantly compared to the LPS-injected group. We did not observe any significant differences among the PBS-injected groups. Taken together, TNF-伪 antagonist CIAM compound, was found to accelerate bone formation under LPS-induced inflammatory condition.