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Nitrogen-containing bisphosphonate, YM529/ONO-5920 (a novel minodronic acid), inhibits RANKL expression in a cultured bone marrow stromal cell line ST2.
Biochem Biophys Res Commun. 2005 Mar 04; 328(1):91-7.BB

Abstract

Increase in bone resorption by osteoclasts can cause metabolic bone diseases, such as osteoporosis. Recent attention has been paid to the receptor activator of the NF-kappaB ligand (RANKL), an accelerator of osteoclast differentiation. RANKL is expressed on the bone marrow-derived stromal cell membrane and induces the differentiation of osteoclasts by binding to RANK expressed on the osteoclast precursor cell membrane. Since the inhibition of RANKL expression can lead to the inhibition of osteoclastic bone resorption, the clinical application of RANKL inhibition could be expected to have a major effect on metabolic bone disease therapy. In this study, we investigated whether or not YM529/ONO-5920, a nitrogen-containing bisphosphonate (a novel minodronic acid), inhibits RANKL expression in a bone marrow-derived stromal cell line (ST2 cells). Reverse transcription-polymerase chain reaction revealed that the administration of YM529/ONO-5920 to ST2 cells inhibited RANKL mRNA expression and reduced RANKL proteins as assessed by Western blot analysis. The inhibition of RANKL mRNA expression was reversed when geranylgeranyl pyrophosphate (GGPP), an intermediate in the mevalonate pathway, was used in combination. Furthermore, YM529/ONO-5920 reduced phosphorylated extracellular signal-regulated kinase 1/2 (ERK1/2), and similarly, U0126, a mitogen-activated protein kinase kinase 1/2 inhibitor, inhibited RANKL expression. Pretreatment with GGPP reversed the YM529/ONO-5920-induced decrease in phosphorylation of ERK. Furthermore, YM529/ONO-5920 decreased TRAP-positive cells in co-culture of ST2 cells and an osteoclast cell line, C7 cells, and this decrease was inhibited by pretreatment with GGPP. This indicates that YM529/ONO-5920 inhibits GGPP biosynthesis in the mevalonate pathway and then signal transduction in the Ras-mitogen-activated protein kinase pathway, thereby inhibiting RANKL expression on ST2 cells. These results suggest a newly elucidated action of bisphosphonates in the inhibition of bone resorption.

Authors+Show Affiliations

Division of Pharmacotherapy, Kinki University School of Pharmaceutical Sciences, 3-4-1 Kowakae, Higashi-Osaka 577-8502, Japan. nishida@phar.kindai.ac.jpNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article

Language

eng

PubMed ID

15670755

Citation

Nishida, Shozo, et al. "Nitrogen-containing Bisphosphonate, YM529/ONO-5920 (a Novel Minodronic Acid), Inhibits RANKL Expression in a Cultured Bone Marrow Stromal Cell Line ST2." Biochemical and Biophysical Research Communications, vol. 328, no. 1, 2005, pp. 91-7.
Nishida S, Tsubaki M, Hoshino M, et al. Nitrogen-containing bisphosphonate, YM529/ONO-5920 (a novel minodronic acid), inhibits RANKL expression in a cultured bone marrow stromal cell line ST2. Biochem Biophys Res Commun. 2005;328(1):91-7.
Nishida, S., Tsubaki, M., Hoshino, M., Namimatsu, A., Uji, H., Yoshioka, S., Tanimori, Y., Yanae, M., Iwaki, M., & Irimajiri, K. (2005). Nitrogen-containing bisphosphonate, YM529/ONO-5920 (a novel minodronic acid), inhibits RANKL expression in a cultured bone marrow stromal cell line ST2. Biochemical and Biophysical Research Communications, 328(1), 91-7.
Nishida S, et al. Nitrogen-containing Bisphosphonate, YM529/ONO-5920 (a Novel Minodronic Acid), Inhibits RANKL Expression in a Cultured Bone Marrow Stromal Cell Line ST2. Biochem Biophys Res Commun. 2005 Mar 4;328(1):91-7. PubMed PMID: 15670755.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Nitrogen-containing bisphosphonate, YM529/ONO-5920 (a novel minodronic acid), inhibits RANKL expression in a cultured bone marrow stromal cell line ST2. AU - Nishida,Shozo, AU - Tsubaki,Masanobu, AU - Hoshino,Mayumi, AU - Namimatsu,Ayumi, AU - Uji,Hiromi, AU - Yoshioka,Shohei, AU - Tanimori,Yoshihiro, AU - Yanae,Masashi, AU - Iwaki,Masahiro, AU - Irimajiri,Kiyohiro, PY - 2004/12/04/received PY - 2005/1/27/pubmed PY - 2005/3/29/medline PY - 2005/1/27/entrez SP - 91 EP - 7 JF - Biochemical and biophysical research communications JO - Biochem Biophys Res Commun VL - 328 IS - 1 N2 - Increase in bone resorption by osteoclasts can cause metabolic bone diseases, such as osteoporosis. Recent attention has been paid to the receptor activator of the NF-kappaB ligand (RANKL), an accelerator of osteoclast differentiation. RANKL is expressed on the bone marrow-derived stromal cell membrane and induces the differentiation of osteoclasts by binding to RANK expressed on the osteoclast precursor cell membrane. Since the inhibition of RANKL expression can lead to the inhibition of osteoclastic bone resorption, the clinical application of RANKL inhibition could be expected to have a major effect on metabolic bone disease therapy. In this study, we investigated whether or not YM529/ONO-5920, a nitrogen-containing bisphosphonate (a novel minodronic acid), inhibits RANKL expression in a bone marrow-derived stromal cell line (ST2 cells). Reverse transcription-polymerase chain reaction revealed that the administration of YM529/ONO-5920 to ST2 cells inhibited RANKL mRNA expression and reduced RANKL proteins as assessed by Western blot analysis. The inhibition of RANKL mRNA expression was reversed when geranylgeranyl pyrophosphate (GGPP), an intermediate in the mevalonate pathway, was used in combination. Furthermore, YM529/ONO-5920 reduced phosphorylated extracellular signal-regulated kinase 1/2 (ERK1/2), and similarly, U0126, a mitogen-activated protein kinase kinase 1/2 inhibitor, inhibited RANKL expression. Pretreatment with GGPP reversed the YM529/ONO-5920-induced decrease in phosphorylation of ERK. Furthermore, YM529/ONO-5920 decreased TRAP-positive cells in co-culture of ST2 cells and an osteoclast cell line, C7 cells, and this decrease was inhibited by pretreatment with GGPP. This indicates that YM529/ONO-5920 inhibits GGPP biosynthesis in the mevalonate pathway and then signal transduction in the Ras-mitogen-activated protein kinase pathway, thereby inhibiting RANKL expression on ST2 cells. These results suggest a newly elucidated action of bisphosphonates in the inhibition of bone resorption. SN - 0006-291X UR - https://www.unboundmedicine.com/medline/citation/15670755/Nitrogen_containing_bisphosphonate_YM529/ONO_5920__a_novel_minodronic_acid__inhibits_RANKL_expression_in_a_cultured_bone_marrow_stromal_cell_line_ST2_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0006-291X(04)02961-4 DB - PRIME DP - Unbound Medicine ER -