Nitrogen-containing bisphosphonates inhibit RANKL- and M-CSF-induced osteoclast formation through the inhibition of ERK1/2 and Akt activation

Journal of Biomedical Science

Shozo Nishida⁵  Takao Satou²  Katsuhiko Sakaguchi¹  Junji Mukai⁴  Daiichiro Fujiwara¹  Kenji Mashimo¹  Naoki Ogawa⁴  Tomoya Takeda⁵  Hirotaka Shimaoka⁵  Kotaro Sakamoto⁵  Motohiro Imano³  Tatsuki Itoh²  Makiko Komai⁵  Masanobu Tsubaki⁵ 

[1] Department of Pharmacy, Japanese Red Cross Society Wakayama Medical Center, Wakayama, Japan;Department of Pathology, Kinki University School of Medicine, Osakasayama, Osaka, Japan;Department of Surgery, Kinki University School of Medicine, Osakasayama, Osaka, Japan;Department of Pharmacy, Izumi Municipal Hospital, Izumi, Osaka, Japan;Division of Pharmacotherapy, Kinki University School of Pharmacy, Kowakae, Higashi-Osaka 577-8502, Japan

关键词: PI3K;    MEK1/2;    Geranylgeranyl pyrophosphate;    Nitrogen-containing bisphosphonate;   

Others  :  821214
DOI  :  10.1186/1423-0127-21-10

 received in 2013-09-18, accepted in 2014-01-20,  发布年份 2014

【 摘 要 】

Background

Bisphosphonates are an important class of antiresorptive drugs used in the treatment of metabolic bone diseases. Recent studies have shown that nitrogen-containing bisphosphonates induced apoptosis in rabbit osteoclasts and prevented prenylated small GTPase. However, whether bisphosphonates inhibit osteoclast formation has not been determined. In the present study, we investigated the inhibitory effect of minodronate and alendronate on the osteoclast formation and clarified the mechanism involved in a mouse macrophage-like cell lines C7 and RAW264.7.

Results

It was found that minodronate and alendronate inhibited the osteoclast formation of C7 cells induced by receptor activator of NF-κB ligand and macrophage colony stimulating factor, which are inhibited by the suppression of geranylgeranyl pyrophosphate (GGPP) biosynthesis. It was also found that minodronate and alendronate inhibited the osteoclast formation of RAW264.7 cells induced by receptor activator of NF-κB ligand. Furthermore, minodronate and alendornate decreased phosphorylated extracellular signal-regulated kinase 1/2 (ERK1/2) and Akt; similarly, U0126, a mitogen protein kinase kinase 1/2 (MEK1/2) inhibitor, and LY294002, a phosphatidylinositol 3-kinase (PI3K) inhibitor, inhibited osteoclast formation.

Conclusions

This indicates that minodronate and alendronate inhibit GGPP biosynthesis in the mevalonate pathway and then signal transduction in the MEK/ERK and PI3K/Akt pathways, thereby inhibiting osteoclast formation. These results suggest a novel effect of bisphosphonates that could be effective in the treatment of bone metabolic diseases, such as osteoporosis.

【 授权许可】

   
2014 Tsubaki et al.; licensee BioMed Central Ltd.

【 图 表 】

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