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The binding of pyrophosphate and two diphosphonates by hydroxyapatite crystals

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Abstract

The binding on hydroxyapatite has been studied of inorganic pyrophosphate (PPj) and two diphosphonates, disodium ethane-1-hydroxy-1,1-diphosphonate (EHDP) and disodium dichloromethylene diphosphonate (Cl2MDP). The binding is greatest for PPi, less for EHDP and least for Cl2MDP. The binding of all three is accompanied by a release of orthophosphate into the solution and an uptake of calcium by the crystals. A competition exists between EHDP and PPi, EHDP being more potent in displacing PPi than the reverse. An analysis with Scatchard plots suggests that the binding is not restricted to one class of binding sites with equal affinity and that the affinity of the first site is in the order EHDP>PPi>Cl2MDP. The results correlate well with previous data on the effect of these compounds on apatite crystal formation and dissolutionin vitro and on bone formation and resorptionin vivo

Résumé

La liaison du pyrophosphate inorganique (PPi) et de deux diphosphonates, l’éthane-1-hydroxy-1,1-diphosphonate disodique (EHDP) et le dichlorométhylène diphosphonate disodique (Cl2MDP), sur l’hydroxyapatite a été étudiée. Le PPi est lié plus fortement que l’EHDP, tandis que le Cl2MDP se lie le moins fortement. La liaison de ces trois substances s’accompagne d’une libération d’orthophosphate dans la solution et d’une adsorption de calcium par les cristaux. Il existe une compétition entre l’EHDP et le PPi; la capacié de l’EHDP à déplacer le PPi est plus grande que celle du PPi à déplacer l’EHDP. L’analyse des résultats à l’aide des fonctions de Scatchard suggère que la liaison n’est pas limitée à une catégorie de sites de liaison ayant une affinité constante et que l’affinité du premier site de liaison est plus grande pour l’EHDP que pour le PPi et plus grande pour le PPi que pour le Cl2MDP. Ces résultats sont en accord avec des résultats précédents concernant l’effet de ces composés sur la formation et la dissolution de cristaux d’apatitein vitro et la formation et la résorption osseusein vivo.

Zusammenfassung

Die Bindung von anorganischem Pyrophosphat (PPi) und zwei Diphosphonaten—Dinatrium-Äthan-1-hydroxy-1,1-diphosphonat (EHDP) und Dinatrium-Dichloromethylen-Diphosphonat (Cl2MDP)—an Hydroxyapatit wurde untersucht. Die Bindung ist am stärksten bei PPi, schwächer bei EHDP und am schwächsten bei Cl2MDP. Bei der Bindung aller drei Substanzen erfolgt gleichzeitig eine Abgabe von Orthophosphat in die Lösung und eine Aufnahme von Calcium durch die Kristalle. Es besteht eine Kompetition zwischen EHDP und PPi, wobei EHDP stärker ist im Verdrängen von PPi als umgekehrt. Eine Analyse mit Scatchard-Kurven weist darauf hin, daß die Bindung nicht auf eine Klasse von Stellen mit konstanter Affinität beschränkt ist und daß die Affinität der ersten Bindungsstelle die Reihenfolge EHDP>PPi>Cl2MDP hat. Die Resultate stimmen gut überein mit früheren Befunden über die Wirkung dieser Verbindungen auf die Bildung und Auflösung von Apatitkristallenin vitro und auf die Knochenbildung und-resorptionin vivo.

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References

  • Bassett, C. A. L., Donath, A., Macagno, F., Preising, R., Fleisch, H., Francis, M. D.: Diphosphonates in the treatment of myositis ossificans. Lancet1969 II, 845.

  • Bisaz, S., Russell, R. G. G., Fleisch, H.: Isolation of inorganic pyrophosphate from bovine and human teeth. Arch. oral Biol.13, 683–696 (1968).

    Article  PubMed  CAS  Google Scholar 

  • Bliznakov, G.: Sur le mécanisme de l’action des additifs adsorbants dans la croissance cristalline. In: Adsorption et croissance cristalline, p. 291–301. Paris: Editions du Centre National de la Recherche Scientifique 1965.

    Google Scholar 

  • Burton, F. G., Neuman, M. W., Neuman, W. F.: On the possible role of crystals in the origin of life. I. The adsorption of nucleosides, nucleotides and pyrophosphate by apatite crystals. Curr. mod. Biol.3, 20–26 (1969).

    PubMed  CAS  Google Scholar 

  • Chen, P. S., Toribara, T. Y., Warner, H.: Microdetermination of phosphorus. Analyt. Chem.28, 1756–1758 (1956).

    Article  CAS  Google Scholar 

  • Dallemagne, M. J.: Le calcium dans le squelette et les dents. Section A: Apatites, phosphates calciques de synthèse, sels osseux et dentaires. In: Handbuch der experimentellen Pharmakologie, Bd. XVII/2, S. 273. Berlin-Göttingen-Heidelberg-New York: Springer 1964.

    Google Scholar 

  • Damme, M. A. van: The influence of ferrocyanide complexes on the dissolution of sodium chloride. In: Adsorption et croissance cristalline, p. 433–449. Paris: Editions du Centre National de la Recherche Scientifique 1965.

    Google Scholar 

  • Fleisch, H., Bisaz, S.: Isolation from urine of pyrophosphate, a calcification inhibitor. Amer. J. Physiol.203, 671–675 (1962).

    PubMed  CAS  Google Scholar 

  • Fleisch, H., Maerki, J., Russell, R. G. G.: Effect of pyrophosphate on dissolution of hydroxyapatite and its possible importance in calcium homeostasis. Proc. Soc. exp. Biol. Med. (N. Y.)122, 317–320 (1966a).

    CAS  Google Scholar 

  • Fleisch, H., Russell, R. G. G.: Pyrophosphate and polyphosphate. Chap. 3 in the International Encyclopedia of Pharmacology and Therapeutics, sect. 51 (G. Peters and C. Radouco-Thomas eds.), p. 61–100. London: Pergamon Press 1970.

    Google Scholar 

  • Fleisch, H., Russel, R. G. G., Bisaz, S., Casey, P. A., Mühlbauer, R. C.: The influence of pyrophosphate analogues (diphosphonates) on the precipitation and dissolution of calcium phosphatein vitro andin vivo. Calc. Tiss. Res.2, Suppl. 10–10A (1968).

    Article  Google Scholar 

  • Fleisch, H., Russell, R. G. G., Bisaz, S., Mühlbauer, R. C., Williams, D. A.: The inhibitory effect of phosphonates on the formation of calcium phosphate crystalsin vitro and on aortic and kidney calcificationin vivo. Europ. J. clin. Invest.1, 12–18 (1970).

    PubMed  CAS  Google Scholar 

  • Fleisch, H., Russell, R. G. G., Francis, M. D.: Diphosphonates inhibit hydroxyapatite dissolutionin vitro and bone resorption in tissue culture andin vivo. Science165, 1262–1264 (1969).

    Article  PubMed  CAS  Google Scholar 

  • Fleisch, H., Russell, R. G. G., Straumann, F.: Effect of pyrophosphate on hydroxyapatite and its implications in calcium homeostasis. Nature (Lond.)212 901–903 (1966b).

    Article  CAS  Google Scholar 

  • Francis, M. D.: The inhibition of calcium hydroxyapatite crystal growth by polyphosphates. Calc. Tiss. Res.3, 151–162 (1969).

    Article  CAS  Google Scholar 

  • Francis, M. D., Russell, R. G. G., Fleisch, H.: Diphosphonates inhibit formation of calcium phosphate crystalsin vitro and pathological calcificationin vivo. Science165, 1264–1266 (1969).

    Article  PubMed  CAS  Google Scholar 

  • Gasser, A. B., Morgan, D. B., Fleisch, H., Richelle, L. J.: The influence of two diphosphonates on calcium metabolism in the rat. Clin. Sci.43, 31–45 (1972).

    PubMed  CAS  Google Scholar 

  • Glasstone, S.: Textbook of physical chemistry, 2nd edit. Princeton, N.J.: D. van Nostrand Company, Inc. 1946.

    Google Scholar 

  • Hall, R. J.: An improved method for the microdetermination of inorganic phosphate in small volumes of biological fluids. J. med. Lab. Technol.20, 97–103 (1963).

    PubMed  CAS  Google Scholar 

  • Jowsey, J., Holley, K. E., Linman, J. W.: Effect of sodium etidronate in adult cats. J. Lab. clin. Med.76, 126–133 (1970).

    PubMed  CAS  Google Scholar 

  • King, W. R., Francis, M. D., Michael, W. R.: Effect of disodium ethane-1-hydroxy-1,1-diphosphonate on bone formation. Clin. Orthop. No78, 251–270 (1971).

    Article  PubMed  CAS  Google Scholar 

  • Krane, S. M., Glimcher, M. J.: Transphosphorylation from nucleoside di-and triphosphates by apatite crystals. J. biol. Chem.237, 2991–2998 (1962).

    PubMed  CAS  Google Scholar 

  • Levinskas, G. J.: Ph.D. Thesis, p. 47 and 84. New York: University of Rochester 1953.

  • Miura, M., Naono, H.: The effect of several condensed phosphates on the dissolution of strontium sulfate. Bull. chem. Soc. Jap.38, 492–495 (1965).

    Article  CAS  Google Scholar 

  • Mutaftschiev, B., Chajes, H., Gindt, R.: Cinétique de dissolution de NaCl et adsorption des ions cadmium. In: Adsorption et croissance cristalline, p. 419–432. Paris: Editions du Centre National de la Recherche Scientifique 1965.

    Google Scholar 

  • Orimo, H., Fujita, T., Yoshikawa, M.: Pyrophosphate enhancement of hypocalcemic effect of thyrocalcitonin in rats. Endocr. jap.16, 309–313 (1969).

    CAS  Google Scholar 

  • Rasmussen, H., Feinblatt, J., Nagata, N., DeLong, A.: Regulation of bone cell function. In: Osteoporosis (U. S. Barzel ed.), p. 187–198. New York-London: Grune & Stratton 1970.

    Google Scholar 

  • Robertson, W. G., Morgan, D. B., Fleisch, H., Francis, M. D.: The effects of diphosphonates on the exchangeable and non-exchangeable calcium and phosphate of hydroxyapatite. Biochim. biophys. Acta (Amst.)261, 517–525 (1972).

    CAS  Google Scholar 

  • Russell, R. G. G., Bisaz, S., Donath, A., Morgan, D. B., Fleisch, H.: Inorganic pyrophosphate in plasma in normal persons and in patients with hypophosphatasia, osteogenesis imperfecta and other disorders of bone. J. clin. Invest.50, 961–969 (1971).

    Article  PubMed  CAS  Google Scholar 

  • Russell, R. G. G., Mühlbauer, R. C., Bisaz, S., Williams, D. A., Fleisch, H.: The influence of pyrophosphate, condensed phosphates, phosphonates and other phosphate compounds on the dissolution of hydroxyapatitein vitro and on bone resorption induced by parathyroid hormone in tissue culture and in thyroparathyroidectomised rats. Calc. Tiss. Res.6, 183–196 (1970).

    Article  CAS  Google Scholar 

  • Scatchard, G.: The attractions of proteins for small molecules and ions. Ann. N.Y. Acad. Sci.51, 660–672 (1949).

    Article  CAS  Google Scholar 

  • Schenk, R., Merz, W. A., Mühlbauer, R., Russel, R. G. G., Fleisch, H.: Effect of ethane-1-hydroxy-1, 1-diphosphonate (EHDP) and dichloromethylene diphosphonate (Cl2 MDP) on the calcification and resorption of cartilage and bone in the tibial epiphysis and metaphysis of rats. Calc. Tiss. Res.11, 196–214 (1973).

    CAS  Google Scholar 

  • Schibler, D., Russell, R. G. G., Fleisch, H.: Inhibition by pyrophosphate and polyphosphate of aortic calcification induced by vitamin D3 in rats. Clin. Sci.35, 363–372 (1968).

    PubMed  CAS  Google Scholar 

  • Smith, R., Russell, R. G. G., Bishop, M.: Diphosphonates and Paget’s disease of bone. Lancet1971I, 945–947.

  • Taves, D. R., Reedy, R. C.: A structural basis for the transphosphorylation of nucleotides with hydroxyapatite. Calc. Tiss. Res.3, 284–292 (1969).

    Article  CAS  Google Scholar 

  • Weder, H. J., Bickel, M. H.: Interactions of drugs with proteins. I. Binding of tricyclic thymoleptics to human and bovine plasma proteins. J. pharm. Sci.59, 1505–1507 (1970a).

    Article  PubMed  CAS  Google Scholar 

  • Weder, H. J., Bickel, M. H.: Interactions of drugs with proteins. II. Experimental methods, treatment of experimental data and thermodynamics of the binding reactions of thymoleptic drugs and model dyes. J. pharm. Sci.59, 1563–1569 (1970b).

    Article  PubMed  CAS  Google Scholar 

  • Weiss, I. W., Fisher, L., Phang, J. M.: Diphosphonate therapy in a patient with myositis ossificans progressiva. Ann. intern. Med.74, 933–936 (1971).

    PubMed  CAS  Google Scholar 

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Authors and Affiliations

  1. Institute of Pathophysiology, University of Berne, Hügelweg 2, CH-3012, Berne, Switzerland

    A. Jung, S. Bisaz &  H. Fleisch

  2. Laboratory for Experimental Surgery, Davos

    A. Jung, S. Bisaz &  H. Fleisch

Authors
  1. A. Jung
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  2. S. Bisaz
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  3. H. Fleisch
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To Prof. F. Leuthardt to his 70th birthday.

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Jung, A., Bisaz, S. & Fleisch, H. The binding of pyrophosphate and two diphosphonates by hydroxyapatite crystals. Calc. Tis Res. 11, 269–280 (1973). https://doi.org/10.1007/BF02547227

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  • DOI: https://doi.org/10.1007/BF02547227

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