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The effects of disodium pamidronate on human polymorphonuclear leukocytes and platelets: An in vitro study

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Abstract

Recent reports have indicated that, as well as having antiresorptive effects, bisphosphonates could have an application as anti-inflammatory drugs. Our aim was to investigate whether this anti-inflammatory action could be mediated by the nitric oxide (NO) released by the leukocytes migrating to the site of inflammation. In particular, we investigated in vitro the intracellular calcium concentration ([Ca2+]i), the level of NO released by PMN and platelets, and the PMN myeloperoxidase activity after incubation with disodium pamidronate, since there was a postulated modulatory effect of this aminosubstituted bisphosphonate on leukocytes both in vitro and in vivo. Our data shows that the pamidronate treatment provoked a significant increase in the [Ca2+]i parallel to the enhancement in NO release, suggesting a possible activation of constitutive nitric oxide synthase, while the myeloperoxidase activity was significantly reduced. In conclusion, we hypothesized that treatment with pamidronate could stimulate NO-production by cells present near the bone compartment, thus constituting a protective mechanism against bone resorption occurring during inflammation. In addition, PMN- and platelet-derived NO could act as a negative feed-back signal to restrict the inflammatory processes.

Abbreviations

APD:

disodium pamidronate

BP:

bisphosphonates

[Ca2+]i :

intracellular calcium concentration

MPO:

myeloperoxidase

PMN:

polymorphonuclear leukocytes

ROS:

reactive oxygen species

References

  1. 1.

    Fleisch, H. Bisphosphonates: mechanisms of action. Endocr. Rev. 19 (1998) 80–100.

  2. 2.

    Parfitt, A.M., Mundy, G.R., Roodman, G.D., Hughes, D.E. and Boyce, B.F. A new model for the regulation of bone resorption, with particular reference to the effects of bisphosphonates. J. Bone Miner. Res. 11 (1996) 150–159.

  3. 3.

    Rodan, G.A. and Fleisch, H.A. Bisphosphonates: mechanisms of action. J. Clin. Invest. 97 (1996) 692–2696.

  4. 4.

    Menezes, A.M., Rocha, F.A., Chaves, H.V., Carvalho, C.B., Ribeiro, R.A. and Brito, G.A.Effect of sodium aledronate on alveolar bone resorption in experimental periodontitis in rats. J. Periodontol. 76 (2005) 901–1909.

  5. 5.

    Bukowski, J.F., Dascher, C.C. and Das, H.Alternative bisphosphonate targets and mechanisms of action. Biochem. Biophys. Res. Commun. 328 (2005) 46–750.

  6. 6.

    Corrado, A., Santoro, N. and Cantatore, F.P.Extra-skeletal effects of bisphosphonates. Joint Bone Spine 74 (2007) 32–38.

  7. 7.

    Guignard, S., Job-Deslandre, C., Sayag-Boukris, V. and Kahan, A.Pamidronate treatment in SAPHO syndrome. Joint Bone Spine. 69 (2002) 92–396.

  8. 8.

    Garrett, I.R., Boyce, B.F., Oreffo, R.O., Bonewald, L., Poser, J. and Mundy, G.R.Oxygen-derived free radicals stimulate osteoclastic bone resorption in rodent bone in vitro and in vivo. J. Clin. Invest. 85 (1990) 32–639.

  9. 9.

    Ries, W.L., Key, L.L. Jr. and Rodriguiz. R.M.Nitroblue tetrazolium reduction and bone resorption by osteoclasts in vitro inhibited by a manganese-based superoxide dismutase mimic. J. Bone Miner. Res. 7 (1992) 31–939.

  10. 10.

    Collin-Osdoby, P., Nickols, G.A. and Osdoby, P.Bone cell function, regulation, and communication: a role for nitric oxide. J. Cell. Biochem. 57 (1995) 99–408.

  11. 11.

    Wright, C.D., Mülsch, A., Busse, R. and Osswald, H.Generation of nitric oxide by human neutrophils. Biochem. Biophys. Res. Commun. 160 (1989) 13–819.

  12. 12.

    Nicolini, F.A. and Mehta, J.L.Inhibitory effect of unstimulated neutrophils on platelet aggregation by release of a factor similar to endothelium-derived relaxing factor (EDRF). Biochem. Pharmacol. 40 (1990) 265–2269.

  13. 13.

    Paul-Clark, M., Del Soldato, P., Fiorucci, S., Flower, R.J. and Perretti, M.21-NO-prednisolone is a novel nitric oxide-releasing derivative of prednisolone with enhanced anti-inflammatory properties. Br. J. Pharmacol. 131 (2000) 345-1354.

  14. 14.

    Persson, J., Ekelund, U. and Grände, P.O.Endogenous nitric oxide reduces microvascular permeability and tissue oedema during exercise in cat skeletal muscle. J. Vasc. Res. 40 (2003) 38–546.

  15. 15.

    Pennanen, N., Lapinjoki, S., Urtti, A. and Mönkkönen, J.Effect of liposomal and free bisphosphonates on the IL-1 beta, IL-6 and TNF alpha secretion from RAW 264 cells in vitro. Pharm. Res. 12 (1995) 16–922.

  16. 16.

    Brown, K.K., Henson, P.M., Maclouf, J., Moyle, M., Ely, J.A. and Worthen, G.S. Neutrophil-platelet adhesion: relative roles of platelet P-selectin and neutrophil beta2 (CD18) integrins. Am. J. Respir. Cell. Mol. Biol. 18 (1998) 00–110.

  17. 17.

    Liao, C.H., Hsiech, Y.J. and Lin, Y.C.Celecoxib stimulates respiratory burst through pertussis toxin-sensitive G-protein, a possible signal for β2 -integrin expression on human neutrophils. Eur. J. Pharmacol. 484 (2004) 9–39.

  18. 18.

    Rao, G.H.Measurement of ionized calcium in normal human blood platelets. Anal. Biochem. 169 (1988) 00–404.

  19. 19.

    Mazzanti, L., Rabini, RA, Fumelli, P., Martarelli, D., Staffolani, R., Salvolini, E. and Curatola, G.Altered platelet membrane dynamic properties in type 1 diabetes. Diabetes. 46 (1997) 069–2074.

  20. 20.

    Reid, I.R., Katz, J.M., Ibbertson, H.K. and Gray, D.H.The effects of hydrocortisone, parathyroid hormone and the bisphosphonate, APD, on bone resorption in neonatal mouse calvaria. Calcif. Tissue Int. 38 (1986) 8–43.

  21. 21.

    Grynkiewicz, G., Poenie, M. and Tsien, R.Y.A new generation of Ca2+ indicators with greatly improved fluorescence properties. J. Biol. Chem. 260 (1985) 440–3450.

  22. 22.

    Green, L.C., Wagner, D.A., Glogowski, J., Skipper, P.L., Wishnok, J.S. and Tannenbaum, S.R.Analysis of nitrate, nitrite and [15N] nitrate in biological fluids. Anal. Biochem. 126 (1982) 31–138.

  23. 23.

    Bradford, M.M.A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding. Anal. Biochem. 72 (1976) 48–254.

  24. 24.

    Suzuki, K., Ota, H., Sasagawa, S., Sakatani, T. and Fujikura, T.Assay method for myeloperoxidase in human polymorphonuclear leukocytes. Anal. Biochem. 132 (1983) 45–352.

  25. 25.

    Fitton, A. and McTavish, D.Pamidronate: a review of its pharmacological properties and therapeutic efficacy in resorptive bone disease. Drugs. 41 (1991) 89-318.

  26. 26.

    Van Offel, J.F., Schuerwegh, A.J., Bridts, C.H., Bracke, P.G., Stevens, W.J. and De Clerck, L.S.Influence of cyclic intravenous pamidronate on proinflammatory monocytic cytokine profiles and bone density in rheumatoid arthritis treated with low dose prednisolone and methotrexate. Clin. Exp. Rheumatol. 19 (2001) 3–20.

  27. 27.

    Pietschmann, P., Stohlawetz, P., Brosch, S., Steiner, G., Smolen, J.S. and Peterlik, M.The effect of aledronate on cytokine production, adhesion molecule expression, and transendothelial migration of human peripheral blood mononuclear cells. Calcif. Tissue Int. 63 (1998) 25–330.

  28. 28.

    Chen, L.Y. and Mehta, J.L.Variable effects of L-arginine analogs on L-arginine-nitric oxide pathway in human neutrophils and platelets may relate to different nitric oxide synthase isoforms. J. Pharmacol. Exp. Ther. 276 (1996) 53–257.

  29. 29.

    Sethi, S. and Dikshit, M.Modulation of polymorphonuclear leokocytes function by nitric oxide. Thromb. Res. 100 (2000) 23–247.

  30. 30.

    De La Cruz, J.P., Blanco, E. and Sanchez de la Cuesta, F.Effect of dipyridamole and aspirin on the platelet-neutrophil interaction via the nitric oxide pathway. Eur. J. Pharmacol. 397 (2000) 5–41.

  31. 31.

    Moilanen, E., Vuorinen, P., Kankaanranta, H., Metsä-Ketelä, T. and Vapaatalo, H. Inhibition by nitric oxide-donors of human polymorphonuclear leukocyte functions. Br. J. Pharmacol. 109 (1993) 52–858.

  32. 32.

    Wallace, J.L.Nitric oxide as a regulator of inflammatory processes. Mem. Inst. Oswaldo Cruz 100suppl.1 (2005) 5–9.

  33. 33.

    Casini, A., Ceni, E., Salzano, R., Biondi, P., Parola, M., Galli, A., Foschi, M., Caligiuri, A., Pinzani, M. and Surrenti, C.Neutrophil-derived superoxide anion induces lipid peroxidation and stimulates collagen synthesis in human hepatic stellate cells: role of nitric oxide. Hepatology. 25 (1997) 61–367.

  34. 34.

    Ziche, M., Morbidelli, L., Choudhuri, R., Zhang, H.T., Donnini, S., Granger, H.J. and Bicknell, R.Nitric oxide synthase lies downstream from vascular endothelial growth factor-induced but not basic fibroblastic growth factorinduced angiogenesis. J. Clin. Invest. 99 (1997) 625–2634.

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Correspondence to Eleonora Salvolini.

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Key words

  • Pamidronate
  • Polymorphonuclear leukocytes
  • Platelets
  • Nitric oxide
  • Intracellular calcium
  • Myeloperoxidase activity