Inhibitory effects of bisphosphonates on growth of amoebae of the cellular slime mold Dictyostelium discoideum

Michael John Rogers, D J Watts, R G Russell, X Ji, X Xiong, G M Blackburn, A V Bayless, F H Ebetino

Research output: Contribution to journalArticle

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Abstract

Bisphosphonates are inhibitors of bone resorption and are used increasingly as therapeutic agents for treating clinical disorders of skeletal metabolism. Their mode of action is still not fully understood. The demonstration that methylenebisphosphonate, a simple methylene analog of pyrophosphate, inhibits the axenic growth of amoebae of the slime mold Dictyostelium discoideum and is incorporated into adenine nucleotides suggested that this organism might be useful in elucidating the cellular effects of bisphosphonates. We examined 24 bisphosphonates, including all those of clinical interest as inhibitors of osteoclast-mediated bone resorption in vivo, for their effects on D. discoideum. All the geminal bisphosphonates inhibited growth of Dictyostelium, although the effectiveness of individual compounds varied widely. When the bisphosphonates were ranked there was a remarkable similarity between the order of potency as inhibitors of growth of Dictyostelium and the order of potency as inhibitors of bone resorption. Thus, bisphosphonates with more complex side-chain structures, especially those containing a nitrogen group, were more potent than simple substituted bisphosphonates, some inhibiting Dictyostelium growth even at concentrations below 10 microM. It therefore appears that the mechanism by which bisphosphonates prevent Dictyostelium growth could be similar to the mechanism by which these compounds affect the activity of osteoclasts. Because the mechanisms of action of bisphosphonates on osteoclasts remains unclear, Dictyostelium may provide an additional model for studying the biochemical mode of action of bisphosphonates. Furthermore, these studies suggest that Dictyostelium may also be a convenient organism for rapid evaluation of potentially active bisphosphonates.
Original languageEnglish
Pages (from-to)1029-1039
Number of pages11
JournalJournal of Bone and Mineral Research
Volume9
Issue number7
DOIs
Publication statusPublished - 1 Jul 1994

Fingerprint

Dictyosteliida
Amoeba
Dictyostelium
Diphosphonates
Growth
Osteoclasts
Bone Density Conservation Agents
Growth Inhibitors
Adenine Nucleotides
Bone Resorption

Keywords

  • Animals
  • Bone Resorption
  • Dictyostelium
  • Diphosphonates
  • Dose-Response Relationship, Drug
  • Osteoclasts
  • Structure-Activity Relationship

Cite this

Rogers, M. J., Watts, D. J., Russell, R. G., Ji, X., Xiong, X., Blackburn, G. M., ... Ebetino, F. H. (1994). Inhibitory effects of bisphosphonates on growth of amoebae of the cellular slime mold Dictyostelium discoideum. Journal of Bone and Mineral Research, 9(7), 1029-1039. https://doi.org/10.1002/jbmr.5650090710

Inhibitory effects of bisphosphonates on growth of amoebae of the cellular slime mold Dictyostelium discoideum. / Rogers, Michael John; Watts, D J; Russell, R G; Ji, X; Xiong, X; Blackburn, G M; Bayless, A V; Ebetino, F H.

In: Journal of Bone and Mineral Research, Vol. 9, No. 7, 01.07.1994, p. 1029-1039.

Research output: Contribution to journalArticle

Rogers, MJ, Watts, DJ, Russell, RG, Ji, X, Xiong, X, Blackburn, GM, Bayless, AV & Ebetino, FH 1994, 'Inhibitory effects of bisphosphonates on growth of amoebae of the cellular slime mold Dictyostelium discoideum' Journal of Bone and Mineral Research, vol. 9, no. 7, pp. 1029-1039. https://doi.org/10.1002/jbmr.5650090710
Rogers, Michael John ; Watts, D J ; Russell, R G ; Ji, X ; Xiong, X ; Blackburn, G M ; Bayless, A V ; Ebetino, F H. / Inhibitory effects of bisphosphonates on growth of amoebae of the cellular slime mold Dictyostelium discoideum. In: Journal of Bone and Mineral Research. 1994 ; Vol. 9, No. 7. pp. 1029-1039.
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AB - Bisphosphonates are inhibitors of bone resorption and are used increasingly as therapeutic agents for treating clinical disorders of skeletal metabolism. Their mode of action is still not fully understood. The demonstration that methylenebisphosphonate, a simple methylene analog of pyrophosphate, inhibits the axenic growth of amoebae of the slime mold Dictyostelium discoideum and is incorporated into adenine nucleotides suggested that this organism might be useful in elucidating the cellular effects of bisphosphonates. We examined 24 bisphosphonates, including all those of clinical interest as inhibitors of osteoclast-mediated bone resorption in vivo, for their effects on D. discoideum. All the geminal bisphosphonates inhibited growth of Dictyostelium, although the effectiveness of individual compounds varied widely. When the bisphosphonates were ranked there was a remarkable similarity between the order of potency as inhibitors of growth of Dictyostelium and the order of potency as inhibitors of bone resorption. Thus, bisphosphonates with more complex side-chain structures, especially those containing a nitrogen group, were more potent than simple substituted bisphosphonates, some inhibiting Dictyostelium growth even at concentrations below 10 microM. It therefore appears that the mechanism by which bisphosphonates prevent Dictyostelium growth could be similar to the mechanism by which these compounds affect the activity of osteoclasts. Because the mechanisms of action of bisphosphonates on osteoclasts remains unclear, Dictyostelium may provide an additional model for studying the biochemical mode of action of bisphosphonates. Furthermore, these studies suggest that Dictyostelium may also be a convenient organism for rapid evaluation of potentially active bisphosphonates.

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