Effects of etidronate on the Enpp1-/- mouse model of generalized arterial calcification of infancy

Huesa,Carmen; Staines,Katherine  A.; Millán,Jose  Luis; MacRae,Vicky  E.

doi:10.3892/ijmm.2015.2212

Effects of etidronate on the Enpp1-/- mouse model of generalized arterial calcification of infancy

Authors:
- Carmen Huesa
- Katherine A. Staines
- Jose Luis Millán
- Vicky E. MacRae
View Affiliations

Affiliations: Roslin Institute and R(D)SVS, The University of Edinburgh, Edinburgh, UK, Sanford Children's Health Research Center, Sanford-Burnham Medical Research Institute, La Jolla, CA, USA
Published online on: May 15, 2015 https://doi.org/10.3892/ijmm.2015.2212
Pages: 159-165
Copyright: © Huesa et al. This is an open access article distributed under the terms of Creative Commons Attribution License [CC BY_NC 3.0].

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

Generalized arterial calcification of infancy (GACI) is an autosomal recessive disorder of spontaneous infantile arterial and periarticular calcification which is attributed to mutations in the ectonucleotide pyrophosphatase/phosphodiesterase 1 (Enpp1) gene. Whilst the bisphosphonate, etidronate, is currently used off-label for the treatment for GACI, recent studies have highlighted its detrimental effects on bone mineralisation. In the present study, we used the Enpp1-/- mouse model of GACI to examine the effects of etidronate treatment (100 µg/kg), on vascular and skeletal calcification. Micro-computed tomography (µCT) analysis revealed a significant decrease in trabecular bone mass, as reflected by the decrease in trabecular bone volume/tissue volume (BV/TV; %), trabecular thickness, trabecular separation, trabecular number and pattern factor (P<0.05) in the Enpp1-/- mice in comparison to the wild-type (WT) mice. Mechanical testing revealed that in the WT mice, treatment with etidronate significantly improved work to fracture and increased work post-failure (P<0.05, in comparison to the vehicle-treated WT mice). This significant increase, however, was not observed in the Enpp1-/- mice. Treatment with etidronate had no effect on bone parameters in the WT mice; however, the Enpp1-/- mice displayed an increased structural model index (SMI; P<0.05). We used a recently developed 3D µCT protocol to reconstruct and quantify the extensive aortic calcification in Enpp1-/- mice in comparison to the WT mice. However, treatment with etidronate did not prevent de novo calcification, and did not arrest the progression of established calcification of the aorta.

View Figures

View References

1	Rutsch F, Ruf N, Vaingankar S, Toliat MR, Suk A, Höhne W, Schauer G, Lehmann M, Roscioli T, Schnabel D, et al: Mutations in ENPP1 are associated with ‘idiopathic’ infantile arterial calcification. Nat Genet. 34:379–381. 2003. View Article : Google Scholar : PubMed/NCBI
2	Rutsch F, Vaingankar S, Johnson K, Goldfine I, Maddux B, Schauerte P, Kalhoff H, Sano K, Boisvert WA, Superti-Furga A, et al: PC-1 nucleoside triphosphate pyrophosphohydrolase defi-ciency in idiopathic infantile arterial calcification. Am J Pathol. 158:543–554. 2001. View Article : Google Scholar : PubMed/NCBI
3	Nitschke Y and Rutsch F: Modulators of networks: Molecular targets of arterial calcification identified in man and mice. Curr Pharm Des. 20:5839–5852. 2014. View Article : Google Scholar : PubMed/NCBI
4	Mackenzie NC, Huesa C, Rutsch F and MacRae VE: New insights into NPP1 function: Lessons from clinical and animal studies. Bone. 51:961–968. 2012. View Article : Google Scholar : PubMed/NCBI
5	Mackenzie NC, Zhu D, Milne EM, van’t Hof R, Martin A, Darryl Quarles L, Millán JL, Farquharson C and MacRae VE: Altered bone development and an increase in FGF-23 expression in Enpp1−/−mice. PLoS One. 7:e321772012. View Article : Google Scholar
6	Apschner A, Huitema LF, Ponsioen B, Peterson-Maduro J and Schulte-Merker S: Zebrafish enpp1 mutants exhibit pathological mineralization, mimicking features of generalized arterial calcification of infancy (GACI) and pseudoxanthoma elasticum (PXE). Dis Model Mech. 7:811–822. 2014. View Article : Google Scholar : PubMed/NCBI
7	Hajjawi MO, MacRae VE, Huesa C, Boyde A, Millán JL, Arnett TR and Orriss IR: Mineralisation of collagen rich soft tissues and osteocyte lacunae in Enpp1−/−mice. Bone. 69:139–147. 2014. View Article : Google Scholar : PubMed/NCBI
8	Li Q, Guo H, Chou DW, Berndt A, Sundberg JP and Uitto J: Mutant Enpp1asj mice as a model for generalized arterial calcification of infancy. Dis Model Mech. 6:1227–1235. 2013. View Article : Google Scholar : PubMed/NCBI
9	Hakim FT, Cranley R, Brown KS, Eanes ED, Harne L and Oppenheim JJ: Hereditary joint disorder in progressive ankylosis (ank/ank) mice. I. Association of calcium hydroxyapatite deposition with inflammatory arthropathy. Arthritis Rheum. 27:1411–1420. 1984. View Article : Google Scholar : PubMed/NCBI
10	Terkeltaub R, Rosenbach M, Fong F and Goding J: Causal link between nucleotide pyrophosphohydrolase overactivity and increased intracellular inorganic pyrophosphate generation demonstrated by transfection of cultured fibroblasts and osteoblasts with plasma cell membrane glycoprotein-1. Relevance to calcium pyrophosphate dihydrate deposition disease. Arthritis Rheum. 37:934–941. 1994. View Article : Google Scholar : PubMed/NCBI
11	Addison WN, Azari F, Sørensen ES, Kaartinen MT and McKee MD: Pyrophosphate inhibits mineralization of osteoblast cultures by binding to mineral, up-regulating osteopontin, and inhibiting alkaline phosphatase activity. J Biol Chem. 282:15872–15883. 2007. View Article : Google Scholar : PubMed/NCBI
12	Staines KA, MacRae VE and Farquharson C: The importance of the SIBLING family of proteins on skeletal mineralisation and bone remodelling. J Endocrinol. 214:241–255. 2012. View Article : Google Scholar : PubMed/NCBI
13	Anderson HC: Molecular biology of matrix vesicles. Clin Orthop Relat Res. (314): 266–280. 1995.PubMed/NCBI
14	Moss DW, Eaton RH, Smith JK and Whitby LG: Association of inorganic-pyrophosphatase activity with human alkaline-phosphatase preparations. Biochem J. 102:53–57. 1967.PubMed/NCBI
15	Majeska RJ and Wuthier RE: Studies on matrix vesicles isolated from chick epiphyseal cartilage. Association of pyrophosphatase and ATPase activities with alkaline phosphatase. Biochim Biophys Acta. 391:51–60. 1975. View Article : Google Scholar : PubMed/NCBI
16	Hessle L, Johnson KA, Anderson HC, Narisawa S, Sali A, Goding JW, Terkeltaub R and Millan JL: Tissue-nonspecific alkaline phosphatase and plasma cell membrane glycoprotein-1 are central antagonistic regulators of bone mineralization. Proc Natl Acad Sci USA. 99:9445–9449. 2002. View Article : Google Scholar : PubMed/NCBI
17	Murshed M, Schinke T, McKee MD and Karsenty G: Extracellular matrix mineralization is regulated locally; different roles of two glacontaining proteins. J Cell Biol. 165:625–630. 2004. View Article : Google Scholar : PubMed/NCBI
18	Macrae VE, Davey MG, McTeir L, Narisawa S, Yadav MC, Millan JL and Farquharson C: Inhibition of PHOSPHO1 activity results in impaired skeletal mineralization during limb development of the chick. Bone. 46:1146–1155. 2010. View Article : Google Scholar : PubMed/NCBI
19	Roberts S, Narisawa S, Harmey D, Millán JL and Farquharson C: Functional involvement of PHOSPHO1 in matrix vesicle-mediated skeletal mineralization. J Bone Miner Res. 22:617–627. 2007. View Article : Google Scholar : PubMed/NCBI
20	Roberts SJ, Owen HC and Farquharson C: Identification of a novel splice variant of the haloacid dehalogenase: PHOSPHO1. Biochem Biophys Res Commun. 371:872–876. 2008. View Article : Google Scholar : PubMed/NCBI
21	Stewart AJ, Roberts SJ, Seawright E, Davey MG, Fleming RH and Farquharson C: The presence of PHOSPHO1 in matrix vesicles and its developmental expression prior to skeletal mineralization. Bone. 39:1000–1007. 2006. View Article : Google Scholar : PubMed/NCBI
22	Yadav MC, Simão AM, Narisawa S, Huesa C, McKee MD, Farquharson C and Millán JL: Loss of skeletal mineralization by the simultaneous ablation of PHOSPHO1 and alkaline phosphatase function: A unified model of the mechanisms of initiation of skeletal calcification. J Bone Miner Res. 26:286–297. 2011. View Article : Google Scholar
23	Narisawa S, Harmey D, Yadav MC, O’Neill WC, Hoylaerts MF and Millán JL: Novel inhibitors of alkaline phosphatase suppress vascular smooth muscle cell calcification. J Bone Miner Res. 22:1700–1710. 2007. View Article : Google Scholar : PubMed/NCBI
24	Sakamoto M, Hosoda Y, Kojimahara K, Yamazaki T and Yoshimura Y: Arthritis and ankylosis in twy mice with hereditary multiple osteochondral lesions: With special reference to calcium deposition. Pathol Int. 44:420–427. 1994. View Article : Google Scholar : PubMed/NCBI
25	Okawa A, Goto S and Moriya H: Calcitonin simultaneously regulates both periosteal hyperostosis and trabecular osteopenia in the spinal hyperostotic mouse (twy/twy) in vivo. Calcif Tissue Int. 64:239–247. 1999. View Article : Google Scholar : PubMed/NCBI
26	Okawa A, Nakamura I, Goto S, Moriya H, Nakamura Y and Ikegawa S: Mutation in Npps in a mouse model of ossification of the posterior longitudinal ligament of the spine. Nat Genet. 19:271–273. 1998. View Article : Google Scholar : PubMed/NCBI
27	Baba H, Furusawa N, Fukuda M, Maezawa Y, Imura S, Kawahara N, Nakahashi K and Tomita K: Potential role of streptozotocin in enhancing ossification of the posterior longitudinal ligament of the cervical spine in the hereditary spinal hyperostotic mouse (twy/twy). Eur J Histochem. 41:191–202. 1997.PubMed/NCBI
28	Furusawa N, Baba H, Imura S and Fukuda M: Characteristics and mechanism of the ossification of posterior longitudinal ligament in the tip-toe walking Yoshimura (twy) mouse. Eur J Histochem. 40:199–210. 1996.PubMed/NCBI
29	Sali A, Favaloro J, Terkeltaub R and Goding J: Germline deletion of the nucleoside triphosphate pyrophosphohydrolase (NTPPPH) plasma cell membrane glycoprotein-1 (PC-1) produces abnormal calcification of periarticular tissues. Ecto-ATPases and Related Ectoenzymes. Vanduffel L and Lemmems R: Shaker Publishing BV; Maastricht, The Netherlands: pp. 267–282. 1999
30	Harmey D, Hessle L, Narisawa S, Johnson KA, Terkeltaub R and Millán JL: Concerted regulation of inorganic pyrophosphate and osteopontin by akp2, enpp1, and ank: An integrated model of the pathogenesis of mineralization disorders. Am J Pathol. 164:1199–1209. 2004. View Article : Google Scholar : PubMed/NCBI
31	Anderson HC, Harmey D, Camacho NP, Garimella R, Sipe JB, Tague S, Bi X, Johnson K, Terkeltaub R and Millán JL: Sustained osteomalacia of long bones despite major improvement in other hypophosphatasia-related mineral deficits in tissue nonspecific alkaline phosphatase/nucleotide pyrophosphatase phosphodi-esterase 1 double-deficient mice. Am J Pathol. 166:1711–1720. 2005. View Article : Google Scholar : PubMed/NCBI
32	Johnson K, Goding J, Van Etten D, Sali A, Hu SI, Farley D, Krug H, Hessle L, Millán JL and Terkeltaub R: Linked deficiencies in extracellular PP_i and osteopontin mediate pathologic calcification associated with defective PC-1 and ANK expression. J Bone Miner Res. 18:994–1004. 2003. View Article : Google Scholar : PubMed/NCBI
33	Russell RG: Bisphosphonates: From bench to bedside. Ann NY Acad Sci. 1068:367–401. 2006. View Article : Google Scholar : PubMed/NCBI
34	Orriss IR, Key ML, Colston KW and Arnett TR: Inhibition of osteoblast function in vitro by aminobisphosphonates. J Cell Biochem. 106:109–118. 2009. View Article : Google Scholar
35	Idris AI, Rojas J, Greig IR, Van’t Hof RJ and Ralston SH: Aminobisphosphonates cause osteoblast apoptosis and inhibit bone nodule formation in vitro. Calcif Tissue Int. 82:191–201. 2008. View Article : Google Scholar : PubMed/NCBI
36	Iwata K, Li J, Follet H, Phipps RJ and Burr DB: Bisphosphonates suppress periosteal osteoblast activity independently of resorption in rat femur and tibia. Bone. 39:1053–1058. 2006. View Article : Google Scholar : PubMed/NCBI
37	Tobias JH, Chow JW and Chambers TJ: 3-Amino-1-hydroxypropylidine-1-bisphosphonate (AHPrBP) suppresses not only the induction of new, but also the persistence of existing bone-forming surfaces in rat cancellous bone. Bone. 14:619–623. 1993. View Article : Google Scholar : PubMed/NCBI
38	Rutsch F, Böyer P, Nitschke Y, Ruf N, Lorenz-Depierieux B, Wittkampf T, Weissen-Plenz G, Fischer RJ, Mughal Z, Gregory JW, et al: GACI Study Group: Hypophosphatemia, hyperphosphaturia, and bisphosphonate treatment are associated with survival beyond infancy in generalized arterial calcification of infancy. Circ Cardiovasc Genet. 1:133–140. 2008. View Article : Google Scholar
39	Chong CR and Hutchins GM: Idiopathic infantile arterial calcification: The spectrum of clinical presentations. Pediatr Dev Pathol. 11:405–415. 2008. View Article : Google Scholar
40	Lomashvili KA, Monier-Faugere MC, Wang X, Malluche HH and O’Neill WC: Effect of bisphosphonates on vascular calcification and bone metabolism in experimental renal failure. Kidney Int. 75:617–625. 2009. View Article : Google Scholar : PubMed/NCBI
41	Otero JE, Gottesman GS, McAlister WH, Mumm S, Madson KL, Kiffer-Moreira T, Sheen C, Millán JL, Ericson KL and Whyte MP: Severe skeletal toxicity from protracted etidronate therapy for generalized arterial calcification of infancy. J Bone Miner Res. 28:419–430. 2013. View Article : Google Scholar
42	Huesa C, Zhu D, Glover JD, Ferron M, Karsenty G, Milne EM, Millan JL, Ahmed SF, Farquharson C, Morton NM, et al: Deficiency of the bone mineralization inhibitor NPP1 protects mice against obesity and diabetes. Dis Model Mech. 7:1341–1350. 2014. View Article : Google Scholar : PubMed/NCBI
43	Sugiyama T, Meakin LB, Galea GL, Jackson BF, Lanyon LE, Ebetino FH, Russell RG and Price JS: Risedronate does not reduce mechanical loading-related increases in cortical and trabecular bone mass in mice. Bone. 49:133–139. 2011. View Article : Google Scholar : PubMed/NCBI
44	Huesa C, Millán JL, van’t Hof RJ and MacRae VE: A new method for the quantification of aortic calcification by three-dimensional micro-computed tomography. Int J Mol Med. 32:1047–1050. 2013.PubMed/NCBI
45	Huesa C, Yadav MC, Finnilä MA, Goodyear SR, Robins SP, Tanner KE, Aspden RM, Millán JL and Farquharson C: PHOSPHO1 is essential for mechanically competent mineralization and the avoidance of spontaneous fractures. Bone. 48:1066–1074. 2011. View Article : Google Scholar : PubMed/NCBI
46	Hildebrand T and Ruegsegger P: A new method for the model-independent assessment of thickness in three-dimensional images. J Microscopy (Oxford). 185:67–75. 1997. View Article : Google Scholar
47	Li Q and Uitto J: Mineralization/anti-mineralization networks in the skin and vascular connective tissues. Am J Pathol. 183:10–18. 2013. View Article : Google Scholar : PubMed/NCBI
48	Black DM, Greenspan SL, Ensrud KE, Palermo L, McGowan JA, Lang TF, Garnero P, Bouxsein ML, Bilezikian JP and Rosen CJ: PaTH Study Investigators: The effects of parathyroid hormone and alendronate alone or in combination in postmenopausal osteoporosis. N Engl J Med. 349:1207–1215. 2003. View Article : Google Scholar : PubMed/NCBI
49	Fleisch H, Russell RG and Straumann F: Effect of pyrophosphate on hydroxyapatite and its implications in calcium homeostasis. Nature. 212:901–903. 1966. View Article : Google Scholar : PubMed/NCBI
50	Felix R, Herrmann W and Fleisch H: Stimulation of precipitation of calcium phosphate by matrix vesicles. Biochem J. 170:681–691. 1978.PubMed/NCBI
51	Thiaville A, Smets A, Clercx A and Perlmutter N: Idiopathic infantile arterial calcification: A surviving patient with renal artery stenosis. Pediatr Radiol. 24:506–508. 1994. View Article : Google Scholar : PubMed/NCBI
52	Van Dyck M, Proesmans W, Van Hollebeke E, Marchal G and Moerman P: Idiopathic infantile arterial calcification with cardiac, renal and central nervous system involvement. Eur J Pediatr. 148:374–377. 1989. View Article : Google Scholar : PubMed/NCBI
53	Thomas T, Lafage MH and Alexandre C: Atypical osteomalacia after 2 year etidronate intermittent cyclic administration in osteoporosis. J Rheumatol. 22:2183–2185. 1995.PubMed/NCBI
54	Silverman SL, Hurvitz EA, Nelson VS and Chiodo A: Rachitic syndrome after disodium etidronate therapy in an adolescent. Arch Phys Med Rehabil. 75:118–120. 1994.PubMed/NCBI
55	Russell RG, Smith R, Preston C, Walton RJ and Woods CG: Diphosphonates in Paget’s disease. Lancet. 1:894–898. 1974.PubMed/NCBI
56	Smith R, Russell RG and Woods CG: Myositis ossificans progressiva. Clinical features of eight patients and their response to treatment. J Bone Joint Surg Br. 58:48–57. 1976.PubMed/NCBI
57	Kim S, Seiryu M, Okada S, Kuroishi T, Takano-Yamamoto T, Sugawara S and Endo Y: Analgesic effects of the non-nitrogen-containing bisphosphonates etidronate and clodronate, independent of anti-resorptive effects on bone. Eur J Pharmacol. 699:14–22. 2013. View Article : Google Scholar
58	Li Q, Sundberg JP, Levine MA, Terry SF and Uitto J: The effects of bisphosphonates on ectopic soft tissue mineralization caused by mutations in the ABCC6gene. Cell Cycle. 14:1082–1089. 2015. View Article : Google Scholar