Effects of bisphosphonates on the inflammatory processes of activated macrophages

J Monkkonen, N Makkonen, M J Rogers, J C Frith, S Auriola

Research output: Contribution to journalArticle

7 Citations (Scopus)

Abstract

All bisphosphonates are similar in terms of their inhibitory effects on bone resorption, but seems to have different effects on inflammatory precesses. For example, clodronate and tiludronate have anti-inflammatory and antiarthritic activity in animals, while aminobisphosphonates exacerbate experimental arthritis in mice. Further, aminobisphosphonate induce acute phase response in patients, while non-aminobisphosphonates do not. During the last few years, we have explored the effects of various bisphosphonates on the inflammatory processes in activated macrophages in vitro.

Clodronate and tiludronate can inhibit proinflammatory cytokine and nitric oxide (NO) secretion from macrophages. In contrast, alendronate and ibandronate enhances the secretion of IL- 1 beta and IL-6. The intracellular delivery, and, consequently, the effects of bisphosphonates on inflammatory responses in macrophages are considerably increased by the encapsulation of the drugs in liposomes.

Clodronate and tiludronate are metabolised to an ATP-analogue by mammalian cells, while aminobisphosphonates (alendronate, ibandronate) are not. The liposome-encapsulated ATP-analogue of clodronate (AppCCl(2)p) exerts similar effects as clodronate itself on proinflammatory cytokine and NO secretion from macrophages. In macrophages,the production of cytokines and NO is regulated by transcription factors, such as nuclear factor KB (NF-KB). In accordance with the effects on cytokine and NO secretion, clodronate and AppCCl(2)p inhibit the nuclear localization of NF-kappa B in activated macrophages, while alendronate enhances it.

The data thus strongly suggest that bisphosphonates can be grouped into those that are metabolised by macrophages and that are capable of inhibiting inflammatory responses in macrophages, thus having potential anti-inflammatory action, and those that are not metabolised and are not anti-inflammatory.

Original languageEnglish
Pages (from-to)321-324
Number of pages4
JournalPhosphorus, Sulfur and SIlicon and the Related Elements
Volume146
Publication statusPublished - 1999

Keywords

  • bisphosphonates
  • macrophages
  • inflammation
  • CELLS IN-VITRO
  • NECROSIS-FACTOR-ALPHA
  • ADJUVANT ARTHRITIS
  • CLODRONATE

Cite this

Monkkonen, J., Makkonen, N., Rogers, M. J., Frith, J. C., & Auriola, S. (1999). Effects of bisphosphonates on the inflammatory processes of activated macrophages. Phosphorus, Sulfur and SIlicon and the Related Elements, 146, 321-324.

Effects of bisphosphonates on the inflammatory processes of activated macrophages. / Monkkonen, J ; Makkonen, N ; Rogers, M J ; Frith, J C ; Auriola, S .

In: Phosphorus, Sulfur and SIlicon and the Related Elements, Vol. 146, 1999, p. 321-324.

Research output: Contribution to journalArticle

Monkkonen, J, Makkonen, N, Rogers, MJ, Frith, JC & Auriola, S 1999, 'Effects of bisphosphonates on the inflammatory processes of activated macrophages', Phosphorus, Sulfur and SIlicon and the Related Elements, vol. 146, pp. 321-324.
Monkkonen, J ; Makkonen, N ; Rogers, M J ; Frith, J C ; Auriola, S . / Effects of bisphosphonates on the inflammatory processes of activated macrophages. In: Phosphorus, Sulfur and SIlicon and the Related Elements. 1999 ; Vol. 146. pp. 321-324.
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AU - Makkonen, N

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AU - Auriola, S

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N2 - All bisphosphonates are similar in terms of their inhibitory effects on bone resorption, but seems to have different effects on inflammatory precesses. For example, clodronate and tiludronate have anti-inflammatory and antiarthritic activity in animals, while aminobisphosphonates exacerbate experimental arthritis in mice. Further, aminobisphosphonate induce acute phase response in patients, while non-aminobisphosphonates do not. During the last few years, we have explored the effects of various bisphosphonates on the inflammatory processes in activated macrophages in vitro.Clodronate and tiludronate can inhibit proinflammatory cytokine and nitric oxide (NO) secretion from macrophages. In contrast, alendronate and ibandronate enhances the secretion of IL- 1 beta and IL-6. The intracellular delivery, and, consequently, the effects of bisphosphonates on inflammatory responses in macrophages are considerably increased by the encapsulation of the drugs in liposomes.Clodronate and tiludronate are metabolised to an ATP-analogue by mammalian cells, while aminobisphosphonates (alendronate, ibandronate) are not. The liposome-encapsulated ATP-analogue of clodronate (AppCCl(2)p) exerts similar effects as clodronate itself on proinflammatory cytokine and NO secretion from macrophages. In macrophages,the production of cytokines and NO is regulated by transcription factors, such as nuclear factor KB (NF-KB). In accordance with the effects on cytokine and NO secretion, clodronate and AppCCl(2)p inhibit the nuclear localization of NF-kappa B in activated macrophages, while alendronate enhances it.The data thus strongly suggest that bisphosphonates can be grouped into those that are metabolised by macrophages and that are capable of inhibiting inflammatory responses in macrophages, thus having potential anti-inflammatory action, and those that are not metabolised and are not anti-inflammatory.

AB - All bisphosphonates are similar in terms of their inhibitory effects on bone resorption, but seems to have different effects on inflammatory precesses. For example, clodronate and tiludronate have anti-inflammatory and antiarthritic activity in animals, while aminobisphosphonates exacerbate experimental arthritis in mice. Further, aminobisphosphonate induce acute phase response in patients, while non-aminobisphosphonates do not. During the last few years, we have explored the effects of various bisphosphonates on the inflammatory processes in activated macrophages in vitro.Clodronate and tiludronate can inhibit proinflammatory cytokine and nitric oxide (NO) secretion from macrophages. In contrast, alendronate and ibandronate enhances the secretion of IL- 1 beta and IL-6. The intracellular delivery, and, consequently, the effects of bisphosphonates on inflammatory responses in macrophages are considerably increased by the encapsulation of the drugs in liposomes.Clodronate and tiludronate are metabolised to an ATP-analogue by mammalian cells, while aminobisphosphonates (alendronate, ibandronate) are not. The liposome-encapsulated ATP-analogue of clodronate (AppCCl(2)p) exerts similar effects as clodronate itself on proinflammatory cytokine and NO secretion from macrophages. In macrophages,the production of cytokines and NO is regulated by transcription factors, such as nuclear factor KB (NF-KB). In accordance with the effects on cytokine and NO secretion, clodronate and AppCCl(2)p inhibit the nuclear localization of NF-kappa B in activated macrophages, while alendronate enhances it.The data thus strongly suggest that bisphosphonates can be grouped into those that are metabolised by macrophages and that are capable of inhibiting inflammatory responses in macrophages, thus having potential anti-inflammatory action, and those that are not metabolised and are not anti-inflammatory.

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KW - inflammation

KW - CELLS IN-VITRO

KW - NECROSIS-FACTOR-ALPHA

KW - ADJUVANT ARTHRITIS

KW - CLODRONATE

M3 - Article

VL - 146

SP - 321

EP - 324

JO - Phosphorus, Sulfur and SIlicon and the Related Elements

JF - Phosphorus, Sulfur and SIlicon and the Related Elements

SN - 1042-6507

ER -