Skip to main content

Advertisement

Log in

Effects of pyrophosphate delivery in a peritoneal dialysis solution on bone tissue of apolipoprotein-E knockout mice with chronic kidney disease

  • Original Article
  • Published:
Journal of Bone and Mineral Metabolism Aims and scope Submit manuscript

Abstract

Vascular calcification (VC) is a risk factor for cardiovascular mortality in the setting of chronic kidney disease (CKD). Pyrophosphate (PPi), an endogenous molecule that inhibits hydroxyapatite crystal formation, has been shown to prevent the development of VC in animal models of CKD. However, the possibility of harmful effects of exogenous administration of PPi on bone requires further investigation. To this end, we examined by histomorphometry the bone of CKD mice after intraperitoneal PPi administration. After CKD creation or sham surgery, 10-week-old female apolipoprotein-E knockout (apoE−/−) mice were randomized to one non-CKD group or 4 CKD groups (n = 10–35/group) treated with placebo or three distinct doses of PPi, and fed with standard diet. Eight weeks later, the animals were killed. Serum and femurs were sampled. Femurs were processed for bone histomorphometry. Placebo-treated CKD mice had significantly higher values of osteoid volume, osteoid surface and bone formation rate than sham-placebo mice with normal renal function. Slightly higher osteoid values were observed in CKD mice in response to very low PPi dose (OV/BV, O.Th and ObS/BS) and, for one parameter measured, to high PPi dose (O.Th), compared to placebo-treated CKD mice. Treatment with PPi did not modify any other structural parameters. Mineral apposition rates, and other parameters of bone formation and resorption were not significantly different among the treated animal groups or control CKD placebo group. In conclusion, PPi does not appear to be deleterious to bone tissue in apoE−/− mice with CKD, although a possible stimulatory PPi effect on osteoid formation may be worth further investigation.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1

Similar content being viewed by others

References

  1. Eknoyan G, Lameire N, Barsoum R, Eckardt KU, Levin A, Levin N, Locatelli F, MacLeod A, Vanholder R, Walker R, Wang H (2004) The burden of kidney disease: improving global outcomes. Kidney Int 66:1310–1314

    Article  PubMed  Google Scholar 

  2. Lameire N, Van Biesen W, Vanholder R (2009) Did 20 years of technological innovations in hemodialysis contribute to better patient outcomes? Clin J Am Soc Nephrol 1:S30–S40

    Article  Google Scholar 

  3. Burke SK (2000) Renagel: reducing serum phosphorus in haemodialysis patients. Hosp Med 61:622–627

    Article  CAS  PubMed  Google Scholar 

  4. Holechek MJ (1991) Medication review: an alternative phosphate binder—calcium acetate. ANNA J 18:321–322

    CAS  PubMed  Google Scholar 

  5. Egrie J (1990) The cloning and production of recombinant human erythropoietin. Pharmacotherapy 10:S3–S8

    Google Scholar 

  6. Depner T, Beck G, Daugirdas J, Kusek J, Eknoyan G (1999) Lessons from the hemodialysis (HEMO) study: an improved measure of the actual hemodialysis dose. Am J Kidney Dis 33:142–149

    Article  CAS  PubMed  Google Scholar 

  7. London GM, Guerin AP, Marchais SJ, Métivier F, Pannier B, Adda H (2003) Arterial media calcification in end-stage renal disease: impact on all-cause and cardiovascular mortality. Nephrol Dial Transplant 18:1731–1740

    Article  PubMed  Google Scholar 

  8. Chiu YW, Adler SG, Budoff MJ, Takasu J, Ashai J, Mehrotra R (2010) Coronary artery calcification and mortality in diabetic patients with proteinuria. Kidney Int 77:1107–1114

    Article  CAS  PubMed  Google Scholar 

  9. Bastos Gonçalves F, Voûte MT, Hoeks SE, Chonchol MB, Boersma EE, Stolker RJ, Verhagen HJ (2012) Calcification of the abdominal aorta as an independent predictor of cardiovascular events: a meta-analysis. Heart 98:988–994

    Article  PubMed  Google Scholar 

  10. Francis MD, Russell RGG, Fleisch H (1969) Diphosphonates inhibit formation of calcium phosphate crystals in vitro and pathologic calcification in vivo. Science 165:1264–1266

    Article  CAS  PubMed  Google Scholar 

  11. Fleisch H, Bisaz S (1962) The inhibitory role of pyrophosphate in calcification. J Physiol 54:340–341

    CAS  Google Scholar 

  12. Shanahan CM, Cary NR, Salisbury JR, Proudfoot D, Weissberg PL, Edmonds ME (1999) Medial localization of mineralization-regulating proteins in association with Monckeberg’s sclerosis: evidence for smooth muscle cell-mediated vascular calcification. Circulation 100:2168–2176

    Article  CAS  PubMed  Google Scholar 

  13. Jung A, Russel RG, Bisaz S, Morgan DB, Fleisch H (1970) Fate of intravenously injected pyrophosphate-32p in dogs. Am J Physiol 218:1757–1764

    CAS  PubMed  Google Scholar 

  14. Lin JH (1996) Bisphosphonates: a review of their pharmacokinetic properties. Bone 18:75–85

    Article  CAS  PubMed  Google Scholar 

  15. Gertz BJ, Holland SD, Kline WF, Matuszewski BK, Freeman A, Quan H, Lasseter KC, Mucklow JC, Porras AG (1995) Studies of the oral bioavailability of alendronate. Clin Pharmacol Ther 58:288–298

    Article  CAS  PubMed  Google Scholar 

  16. O’Neill WC, Lomashvili KA, Malluche HH, Faugere MC, Riser BL (2011) Treatment with pyrophosphate inhibits uremic vascular calcification. Kidney Int 79:512–517

    Article  PubMed Central  PubMed  Google Scholar 

  17. Lomashvili KA, Garg P, Narisawa S, Millan JL, O’Neill WC (2008) Up regulation of alkaline phosphatase and pyrophosphate hydrolysis; potential mechanism for uremic vascular calcification. Kidney Int 73:1024–1030

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  18. Rutsch F, Ruf N, Vaingankar S, Toliat MR, Suk A et al (2003) Mutations in enpp1 are associated with ‘idiopathic’ infantile arterial calcification. Nat Genet 34:379–3781

    Article  CAS  PubMed  Google Scholar 

  19. Lomashvili KA, Khawandi W, O’Neill WC (2005) Reduced plasma pyrophosphate levels in hemodialysis patients. J Am Soc Nephrol 16:2495–2500

    Article  CAS  PubMed  Google Scholar 

  20. Riser BL, Barreto FC, Rezg R, Valaitis PW, Cook CS, White JA, Gass JH, Maizel J, Louvet L, Drueke TB, Holmes CJ, Massy ZA (2011) Daily peritoneal administration of sodium pyrophosphate in a dialysis solution prevents the development of vascular calcification in a mouse model of uraemia. Nephrol Dial Transplant 26:3349–3357

    Article  CAS  PubMed  Google Scholar 

  21. Amerling R, Harbord NB, Pullman J, Feinfeld DA (2010) Bisphosphonate use in chronic kidney disease: association with adynamic bone disease in a bone histology series. Blood Purif 29:293–299

    Article  CAS  PubMed  Google Scholar 

  22. Kidney Disease: Improving Global Outcomes (KDIGO) CKD-MBD Work Group (2009) Kdigo clinical practice guideline for the diagnosis, evaluation, prevention, and treatment of chronic kidney disease-mineral and bone disorder (CKD-MBD). Kidney Int 9:S1–S130

    Google Scholar 

  23. Nikolov IG, Joki N, Nguyen-Khoa T, Ivanovski O, Phan O, Lacour B, Drüeke TB, Massy ZA, Dos Reis LM, Jorgetti V, Lafage-Proust MH (2010) Chronic kidney disease bone and mineral disorder (CKD-MBD) in apolipoprotein E-deficient mice with chronic renal failure. Bone 47:156–163

    Article  CAS  PubMed  Google Scholar 

  24. Parfitt AM, Drezner MK, Glorieux FH, Kanis JA, Malluche H, Meunier PJ, Ott SM, Recker RR (1987) Bone histomorphometry: standardization of nomenclature, symbols, and units. Report of the ASBMR histomorphometry nomenclature committee. J Bone Miner Res 2:595–610

    Article  CAS  PubMed  Google Scholar 

  25. Ivanovski O, Nikolov IG, Joki N, Caudrillier A, Phan O, Mentaverri R, Maizel J, Hamada Y, Nguyen-Khoa T, Fukagawa M, Kamel S, Lacour B, Drüeke TB, Massy ZA (2009) The calcimimetic R-568 retards uremiaenhanced vascular calcification and atherosclerosis in apolipoprotein E deficient (apoE−/−) mice. Atherosclerosis 205:55–62

    Article  CAS  PubMed  Google Scholar 

  26. Massy ZA, Ivanovski O, Nguyen-Khoa T, Angulo J, Szumilak D, Mothu N, Phan O, Daudon M, Lacour B, Drüeke TB, Muntzel MS (2005) Uremia accelerates both atherosclerosis and arterial calcification in apolipoprotein E knockout mice. J Am Soc Nephrol 16:109–116

    Article  CAS  PubMed  Google Scholar 

  27. Zhou X, Cui Y, Zhou X, Han J (2012) Phosphate/pyrophosphate and MV-related proteins in mineralisation: discoveries from mouse models. Int J Biol Sci 8:778–790

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  28. Maruotti N, Corrado A, Neve A, Cantatore FP (2012) Bisphosphonates: effects on osteoblast. Eur J Clin Pharmacol 68:1013–1018

    Article  CAS  PubMed  Google Scholar 

  29. Viereck V, Emons G, Lauck V, Frosch KH, Blaschke S, Gründker C, Hofbauer LC (2002) Bisphosphonates pamidronate and zoledronic acid stimulate osteoprotegerin production by primary human osteoblasts. Biochem Biophys Res Commun 291:680–686

    Article  CAS  PubMed  Google Scholar 

  30. Pan B, Farrugia AN, To LB, Findlay DM, Green J, Lynch K, Zannettino AC (2004) The nitrogen-containing bisphosphonate, zoledronic acid, influences RANKL expression in human osteoblast-like cells by activating TNF-alpha converting enzyme (TACE). J Bone Miner Res 19:147–154

    Article  CAS  PubMed  Google Scholar 

  31. Addison WN, Azari F, Sørensen ES, Kaartinen MT, McKee MD (2007) Pyrophosphate inhibits mineralization of osteoblast cultures by binding to mineral, up-regulating osteopontin, and inhibiting alkaline phosphatase activity. J Biol Chem 282:15872–15883

    Article  CAS  PubMed  Google Scholar 

  32. Foster BL, Nagatomo KJ, Nociti FH Jr, Fong H, Dunn D, Tran AB, Wang W, Narisawa S, Millán JL, Somerman MJ (2012) Central role of pyrophosphate in acellular cementum formation. PLoS One 7:e38393

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  33. Murshed M, Harmey D, Millan JL, McKee MD, Karsenty G (2005) Unique coexpression in osteoblasts of broadly expressed genes accounts for the spatial restriction of ECM mineralization to bone. Genes Dev 19:1093–1104

    Article  CAS  PubMed Central  PubMed  Google Scholar 

Download references

Acknowledgments

The study was supported by a grant from Baxter. We are grateful to Picardie Regional Council and Jules Verne University of Picardie for awarding postdoctoral grants to Fellype C. Barreto and Rodrigo Bueno de Oliveira (who also received a postdoctoral grant from CNPq, Brazil). The authors thank Charlotte Paquet, Jules Verne University of Picardie, for valuable technical help. We also wish to thank Arpita Das, Lianmei Feng, Ahmed Fariyal and Paul Zieski, Baxter Healthcare, for the preparation of the PD solutions.

Conflict of interest

Tilman B. Drüeke declares having received honoraria as a consultant and/or speaker from Shire, Genzyme and Amgen. Ziad A. Massy declares having received honoraria as a consultant and/or speaker from Shire, Genzyme and Amgen. Authors at Baxter Healthcare are employees of a Company with potential commercial interest in this research. Other authors at Inserm Unit-1088, UFR de Médicine/Pharmacie, Amiens and the Division of Nephrology, Amiens University Hospital and Jules Verne University of Picard, Amiens, France have no competing interest.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Ziad A. Massy.

About this article

Cite this article

Barreto, F.C., de Oliveira, R.B., Benchitrit, J. et al. Effects of pyrophosphate delivery in a peritoneal dialysis solution on bone tissue of apolipoprotein-E knockout mice with chronic kidney disease. J Bone Miner Metab 32, 636–644 (2014). https://doi.org/10.1007/s00774-013-0541-y

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00774-013-0541-y

Keywords

Navigation