Nitrogen-containing bisphosphonates inhibit RANKL- and M-CSF-induced osteoclast formation through the inhibition of ERK1/2 and Akt activation.
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.
Masanobu
M
Tsubaki
Makiko
M
Komai
Tatsuki
T
Itoh
Motohiro
M
Imano
Kotaro
K
Sakamoto
Hirotaka
H
Shimaoka
Tomoya
T
Takeda
Naoki
N
Ogawa
Kenji
K
Mashimo
Daiichiro
D
Fujiwara
Junji
J
Mukai
Katsuhiko
K
Sakaguchi
Takao
T
Satou
Division of Pharmacotherapy, Kinki University School of Pharmacy, Kowakae, Higashi-Osaka 577-8502, Japan. nishida@phar.kindai.ac.jp.
Shozo
S
Nishida
D019386:Alendronate / Q000008:administration & dosage*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001851:Bone Diseases, Metabolic / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D004164:Diphosphonates / Q000008:administration & dosage* / Q000737:chemistry; D006801:Humans; D007093:Imidazoles / Q000008:administration & dosage*; D020935:MAP Kinase Signaling System / Q000235:genetics; D016173:Macrophage Colony-Stimulating Factor / Q000378:metabolism; D008264:Macrophages / Q000166:cytology / Q000187:drug effects; D051379:Mice; D009584:Nitrogen / Q000737:chemistry; D051058:Oncogene Protein v-akt / Q000378:metabolism; D010010:Osteoclasts / Q000187:drug effects*; D011106:Polyisoprenyl Phosphates / Q000096:biosynthesis; D053245:RANK Ligand / Q000037:antagonists & inhibitors
D004164:Diphosphonates; D007093:Imidazoles; D011106:Polyisoprenyl Phosphates; D053245:RANK Ligand; C087958:YM 529; D016173:Macrophage Colony-Stimulating Factor; D051058:Oncogene Protein v-akt; C002963:geranylgeranyl pyrophosphate; D009584:Nitrogen; D019386:Alendronate