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Current Osteoporosis Reports
Published in: Current Osteoporosis Reports 4/2017

01-08-2017 | Pediatrics (L Ward and E Imel, Section Editors)

Inherited Arterial Calcification Syndromes: Etiologies and Treatment Concepts

Authors: Yvonne Nitschke, Frank Rutsch

Published in: Current Osteoporosis Reports | Issue 4/2017

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Abstract

Purpose of Review

We give an update on the etiology and potential treatment options of rare inherited monogenic disorders associated with arterial calcification and calcific cardiac valve disease.

Recent Findings

Genetic studies of rare inherited syndromes have identified key regulators of ectopic calcification. Based on the pathogenic principles causing the diseases, these can be classified into three groups: (1) disorders of an increased extracellular inorganic phosphate/inorganic pyrophosphate ratio (generalized arterial calcification of infancy, pseudoxanthoma elasticum, arterial calcification and distal joint calcification, progeria, idiopathic basal ganglia calcification, and hyperphosphatemic familial tumoral calcinosis; (2) interferonopathies (Singleton-Merten syndrome); and (3) others, including Keutel syndrome and Gaucher disease type IIIC.

Summary

Although some of the identified causative mechanisms are not easy to target for treatment, it has become clear that a disturbed serum phosphate/pyrophosphate ratio is a major force triggering arterial and cardiac valve calcification. Further studies will focus on targeting the phosphate/pyrophosphate ratio to effectively prevent and treat these calcific disease phenotypes.
Literature
1.
Wayhs R, Zelinger A, Raggi P. High coronary artery calcium scores pose an extremely elevated risk for hard events. J Am Coll Cardiol. 2002;39(2):225–30.PubMedCrossRef
2.
Wilson PW, Kauppila LI, O’Donnell CJ, Kiel DP, Hannan M, Polak JM, et al. Abdominal aortic calcific deposits are an important predictor of vascular morbidity and mortality. Circulation. 2001;103(11):1529–34.PubMedCrossRef
3.
Niskanen LK, Suhonen M, Siitonen O, Lehtinen JM, Uusitupa MI. Aortic and lower limb artery calcification in type 2 (non-insulin-dependent) diabetic patients and non-diabetic control subjects. A five year follow-up study. Atherosclerosis. 1990;84(1):61–71.PubMedCrossRef
4.
5.
Weissen-Plenz G, Nitschke Y, Rutsch F. Mechanisms of arterial calcification: spotlight on the inhibitors. Adv Clin Chem. 2008;46:263–93.PubMedCrossRef
6.
7.
8.
9.
10.
Tintut Y, Patel J, Parhami F, Demer LL. Tumor necrosis factor-alpha promotes in vitro calcification of vascular cells via the cAMP pathway. Circulation. 2000;102(21):2636–42.PubMedCrossRef
11.
12.
Bini A, Mann KG, Kudryk BJ, Schoen FJ. Noncollagenous bone matrix proteins, calcification, and thrombosis in carotid artery atherosclerosis. Arterioscler Thromb Vasc Biol. 1999;19(8):1852–61.PubMedCrossRef
13.
Dhore CR, Cleutjens JP, Lutgens E, Cleutjens KB, Geusens PP, Kitslaar PJ, et al. Differential expression of bone matrix regulatory proteins in human atherosclerotic plaques. Arterioscler Thromb Vasc Biol. 2001;21(12):1998–2003.PubMedCrossRef
14.
Nitschke Y, Rutsch F. Modulators of networks: molecular targets of arterial calcification identified in man and mice. Curr Pharm Des. 2014;20(37):5839–52.PubMedCrossRef
15.
• Rutsch F, MacDougall M, Lu C, Buers I, Mamaeva O, Nitschke Y, et al. A specific IFIH1 gain-of-function mutation causes Singleton-Merten syndrome. Am J Hum Genet. 2015;96(2):275–82. doi:10.​1016/​j.​ajhg.​2014.​12.​014. This paper for the first time links a gain of function mutation in a RIG-I like intracellular receptor for double stranded RNA to arterial and cardiac valve calcification PubMedPubMedCentralCrossRef
16.
Abrahamov A, Elstein D, Gross-Tsur V, Farber B, Glaser Y, Hadas-Halpern I, et al. Gaucher’s disease variant characterised by progressive calcification of heart valves and unique genotype. Lancet. 1995;346(8981):1000–3.PubMedCrossRef
17.
18.
• Feigenbaum A, Muller C, Yale C, Kleinheinz J, Jezewski P, Kehl HG, et al. Singleton-Merten syndrome: an autosomal dominant disorder with variable expression. Am J Med Genet A. 2013;161A(2):360–70. doi:10.​1002/​ajmg.​a.​35732. This case series describes the multi-faceted clinical picture of Singleton-Merten syndrome PubMedCrossRef
19.
Rutsch F, Ruf N, Vaingankar S, Toliat MR, Suk A, Hohne W, et al. Mutations in ENPP1 are associated with “idiopathic” infantile arterial calcification. Nat Genet. 2003;34(4):379–81. doi:10.​1038/​ng1221.PubMedCrossRef
20.
21.
Mastrolia SA, Weintraub AY, Baron J, Sciaky-Tamir Y, Koifman A, Loverro G, et al. Antenatal diagnosis of idiopathic arterial calcification: a systematic review with a report of two cases. Arch Gynecol Obstet. 2015;291(5):977–86. doi:10.​1007/​s00404-014-3567-z.PubMedCrossRef
22.
Felix R, Monod A, Broge L, Hansen NM, Fleisch H. Aggregation of calcium oxalate crystals: effect of urine and various inhibitors. Urol Res. 1977;5(1):21–8.PubMedCrossRef
23.
24.
25.
26.
Dlamini N, Splitt M, Durkan A, Siddiqui A, Padayachee S, Hobbins S, et al. Generalized arterial calcification of infancy: phenotypic spectrum among three siblings including one case without obvious arterial calcifications. Am J Med Genet A. 2009;149A(3):456–60. doi:10.​1002/​ajmg.​a.​32646.PubMedCrossRef
27.
28.
29.
Meradji M, de Villeneuve VH, Huber J, de Bruijn WC, Pearse RG. Idiopathic infantile arterial calcification in siblings: radiologic diagnosis and successful treatment. J Pediatr. 1978;92(3):401–5.PubMedCrossRef
30.
31.
Ferreira C, Ziegler S, Gahl W. Generalized arterial calcification of infancy. In: Pagon RA, Adam MP, Ardinger HH, Wallace SE, Amemiya A, Bean LJH et al., editors. GeneReviews® [Internet]. Seattle (WA) 1993.
32.
33.
•• Otero JE, Gottesman GS, WH MA, Mumm S, Madson KL, Kiffer-Moreira T, et al. Severe skeletal toxicity from protracted etidronate therapy for generalized arterial calcification of infancy. J Bone Miner Res : Off J Am Soc Bone Miner Res. 2013;28(2):419–30. doi:10.​1002/​jbmr.​1752. This paper for the first time describe serious side effects associated with prolonged bisphosphonate therapy in a child with GACI CrossRef
34.
Thomas P, Chandra M, Kahn E, McVicar M, Naidich J, LaCorte M. Idiopathic arterial calcification of infancy: a case with prolonged survival. Pediatr Nephrol. 1990;4(3):233–5.PubMedCrossRef
35.
•• Albright RA, Stabach P, Cao W, Kavanagh D, Mullen I, Braddock AA, et al. ENPP1-FC prevents mortality and vascular calcifications in rodent model of generalized arterial calcification of infancy. Nat Commun. 2015;6:10006. doi:10.​1038/​ncomms10006. In this study, enzyme therapy using recombinant ENPP1 protein coupled to the FC-portion of the IgG protein successfully prevents ectopic calcification in Enpp1 deficient mice PubMedPubMedCentralCrossRef
36.
Ringpfeil F, Pulkkinen L, Uitto J. Molecular genetics of pseudoxanthoma elasticum. Exp Dermatol. 2001;10(4):221–8.PubMedCrossRef
37.
Miksch S, Lumsden A, Guenther UP, Foernzler D, Christen-Zach S, Daugherty C, et al. Molecular genetics of pseudoxanthoma elasticum: type and frequency of mutations in ABCC6. Hum Mutat. 2005;26(3):235–48. doi:10.​1002/​humu.​20206.PubMedCrossRef
38.
39.
Bergen AA, Plomp AS, Schuurman EJ, Terry S, Breuning M, Dauwerse H, et al. Mutations in ABCC6 cause pseudoxanthoma elasticum. Nat Genet. 2000;25(2):228–31. doi:10.​1038/​76109.PubMedCrossRef
40.
Le Saux O, Beck K, Sachsinger C, Silvestri C, Treiber C, Goring HH, et al. A spectrum of ABCC6 mutations is responsible for pseudoxanthoma elasticum. Am J Hum Genet. 2001;69(4):749–64.PubMedPubMedCentralCrossRef
41.
42.
Struk B, Cai L, Zach S, Ji W, Chung J, Lumsden A, et al. Mutations of the gene encoding the transmembrane transporter protein ABC-C6 cause pseudoxanthoma elasticum. J Mol Med. 2000;78(5):282–6.PubMedCrossRef
43.
Aherrahrou Z, Doehring LC, Ehlers EM, Liptau H, Depping R, Linsel-Nitschke P, et al. An alternative splice variant in Abcc6, the gene causing dystrophic calcification, leads to protein deficiency in C3H/He mice. J Biol Chem. 2008;283(12):7608–15. doi:10.​1074/​jbc.​M708290200.PubMedCrossRef
44.
Doehring LC, Kaczmarek PM, Ehlers E, Mayer B, Erdmann J, Schunkert H, et al. Arterial calcification in mice after freeze-thaw injury. Ann Anat = Anatomischer Anzeiger : Off Organ Anatomische Gesellschaft. 2006;188(3):235–42.CrossRef
45.
46.
47.
48.
Le Boulanger G, Labreze C, Croue A, Schurgers LJ, Chassaing N, Wittkampf T, et al. An unusual severe vascular case of pseudoxanthoma elasticum presenting as generalized arterial calcification of infancy. Am J Med Genet A. 2010;152A(1):118–23. doi:10.​1002/​ajmg.​a.​33162.PubMedCrossRef
49.
•• Nitschke Y, Baujat G, Botschen U, Wittkampf T, du Moulin M, Stella J, et al. Generalized arterial calcification of infancy and pseudoxanthoma elasticum can be caused by mutations in either ENPP1 or ABCC6. Am J Hum Genet. 2012;90(1):25–39. doi:10.​1016/​j.​ajhg.​2011.​11.​020. This paper demonstrates the genotypic and phenotypic overlap of GACI and PXE and points to disordered pyrophosphate metabolism as the common pathophysiologic pathway of both disorders PubMedPubMedCentralCrossRef
50.
•• Jansen RS, Kucukosmanoglu A, de Haas M, Sapthu S, Otero JA, IEM H, et al. ABCC6 prevents ectopic mineralization seen in pseudoxanthoma elasticum by inducing cellular nucleotide release. Proc Natl Acad Sci U S A. 2013;110(50):20206–11. doi:10.​1073/​pnas.​1319582110. This study for the first time directly links PXE to disordered ATP and pyrophosphate metabolism PubMedPubMedCentralCrossRef
51.
Jansen RS, Duijst S, Mahakena S, Sommer D, Szeri F, Varadi A, et al. ABCC6-mediated ATP secretion by the liver is the main source of the mineralization inhibitor inorganic pyrophosphate in the systemic circulation-brief report. Arterioscler Thromb Vasc Biol. 2014;34(9):1985–9. doi:10.​1161/​ATVBAHA.​114.​304017.PubMedCrossRef
52.
53.
54.
LaRusso J, Li Q, Jiang Q, Uitto J. Elevated dietary magnesium prevents connective tissue mineralization in a mouse model of pseudoxanthoma elasticum (Abcc6(−/−)). J Investig Dermatol. 2009;129(6):1388–94. doi:10.​1038/​jid.​2008.​391.PubMedCrossRef
55.
•• Li Q, Sundberg JP, Levine MA, Terry SF, Uitto J. The effects of bisphosphonates on ectopic soft tissue mineralization caused by mutations in the ABCC6 gene. Cell Cycle. 2015;14(7):1082–9. doi:10.​1080/​15384101.​2015.​1007809. Based on the observation of low extracellular PP i levels in Abcc−/− mice, the authors successfully used synthetic PP i analogs to prevent ectopic mineralization in this animal model PubMedPubMedCentralCrossRef
56.
Li Q, Kingman J, Sundberg JP, Levine MA, Uitto J. Etidronate prevents, but does not reverse, ectopic mineralization in a mouse model of pseudoxanthoma elasticum (Abcc6−/−). Oncotarget. 2016; doi:10.​18632/​oncotarget.​10738.
57.
•• Pomozi V, Brampton C, Szeri F, Dedinszki D, Kozak E, van de Wetering K, et al. Functional rescue of ABCC6 deficiency by 4-phenylbutyrate therapy reduces dystrophic calcification in Abcc6−/− mice. J Investig Dermatol. 2016; doi:10.​1016/​j.​jid.​2016.​10.​035. This study describes the successful use of 4-PBA, a pharmacological chaperone as an allele specific therapy to treat dystrophic calcification in a mouse model of PXE PubMedCrossRef
58.
•• St Hilaire C, Ziegler SG, Markello TC, Brusco A, Groden C, Gill F, et al. NT5E mutations and arterial calcifications. N Engl J Med. 2011;364(5):432–42. doi:10.​1056/​NEJMoa0912923. This study for the first time links the rare disorder calcification of joint and arteries (CALJA) to mutations in NT5E encoding CD73, a protein which by degrading AMP generates adenosine PubMedPubMedCentralCrossRef
59.
60.
61.
62.
63.
64.
Sheen CR, Kuss P, Narisawa S, Yadav MC, Nigro J, Wang W, et al. Pathophysiological role of vascular smooth muscle alkaline phosphatase in medial artery calcification. J Bone Miner Res : Off J Am Soc Bone Miner Res. 2015;30(5):824–36. doi:10.​1002/​jbmr.​2420.CrossRef
65.
Savinov AY, Salehi M, Yadav MC, Radichev I, Millan JL, Savinova OV. Transgenic overexpression of tissue-nonspecific alkaline phosphatase (TNAP) in vascular endothelium results in generalized arterial calcification. J Am Heart Assoc. 2015;4(12). doi:10.​1161/​JAHA.​115.​002499.
66.
Gutierrez LB, Link T, Chaganti K, Motamedi D. Arterial calcification due to CD73 deficiency (ACDC): imaging manifestations of ectopic mineralization. Skelet Radiol. 2016;45(11):1583–7. doi:10.​1007/​s00256-016-2465-9.CrossRef
67.
Kimura T, Miura T, Aoki K, Saito S, Hondo H, Konno T, et al. Familial idiopathic basal ganglia calcification: histopathologic features of an autopsied patient with an SLC20A2 mutation. Neuropathol Off J Jpn Soc Neuropathol. 2016;36(4):365–71. doi:10.​1111/​neup.​12280.CrossRef
68.
Hozumi I, Kohmura A, Kimura A, Hasegawa T, Honda A, Hayashi Y, et al. High levels of copper, zinc, iron and magnesium, but not calcium, in the cerebrospinal fluid of patients with Fahr’s disease. Case Rep Neurol. 2010;2(2):46–51. doi:10.​1159/​000313920.PubMedPubMedCentralCrossRef
69.
Wang C, Li Y, Shi L, Ren J, Patti M, Wang T, et al. Mutations in SLC20A2 link familial idiopathic basal ganglia calcification with phosphate homeostasis. Nat Genet. 2012;44(3):254–6. doi:10.​1038/​ng.​1077.PubMedCrossRef
70.
Jensen N, Schroder HD, Hejbol EK, Fuchtbauer EM, de Oliveira JR, Pedersen L. Loss of function of Slc20a2 associated with familial idiopathic basal ganglia calcification in humans causes brain calcifications in mice. J Mol Neurosci : MN. 2013;51(3):994–9. doi:10.​1007/​s12031-013-0085-6.PubMedCrossRef
71.
Wallingford MC, Chia JJ, Leaf EM, Borgeia S, Chavkin NW, Sawangmake C, et al. SLC20A2 deficiency in mice leads to elevated phosphate levels in cerebrospinal fluid and glymphatic pathway-associated arteriolar calcification, and recapitulates human idiopathic basal ganglia calcification. Brain Pathol. 2017;27(1):64–76. doi:10.​1111/​bpa.​12362.PubMedCrossRef
72.
•• Legati A, Giovannini D, Nicolas G, Lopez-Sanchez U, Quintans B, Oliveira JR, et al. Mutations in XPR1 cause primary familial brain calcification associated with altered phosphate export. Nat Genet. 2015;47(6):579–81. doi:10.​1038/​ng.​3289. This study for the first time links the rare disorder IBGC to mutations in XPR1, encoding a phosphate exporter involved in phosphate homeostasis PubMedPubMedCentralCrossRef
73.
74.
75.
•• Nicolas G, Pottier C, Maltete D, Coutant S, Rovelet-Lecrux A, Legallic S, et al. Mutation of the PDGFRB gene as a cause of idiopathic basal ganglia calcification. Neurology. 2013;80(2):181–7. doi:10.​1212/​WNL.​0b013e31827ccf34​. This study for the first time links mutations in PDGFRB to the rare disease IBGC PubMedCrossRef
76.
77.
Sanchez-Contreras M, Baker MC, Finch NA, Nicholson A, Wojtas A, Wszolek ZK, et al. Genetic screening and functional characterization of PDGFRB mutations associated with basal ganglia calcification of unknown etiology. Hum Mutat. 2014;35(8):964–71. doi:10.​1002/​humu.​22582.PubMedPubMedCentralCrossRef
78.
Arts FA, Velghe AI, Stevens M, Renauld JC, Essaghir A, Demoulin JB. Idiopathic basal ganglia calcification-associated PDGFRB mutations impair the receptor signalling. J Cell Mol Med. 2015;19(1):239–48. doi:10.​1111/​jcmm.​12443.PubMedCrossRef
79.
•• Keller A, Westenberger A, Sobrido MJ, Garcia-Murias M, Domingo A, Sears RL, et al. Mutations in the gene encoding PDGF-B cause brain calcifications in humans and mice. Nat Genet. 2013;45(9):1077–82. doi:10.​1038/​ng.​2723. Mutations in the gene encoding PDGF-B, the main ligand for PDGF-RB, were found to cause IBGC. Loss of PDGFB was found to correlate with pericyte and blood-brain barrier deficiency, leading to calcification PubMedCrossRef
80.
Villa-Bellosta R, Levi M, Sorribas V. Vascular smooth muscle cell calcification and SLC20 inorganic phosphate transporters: effects of PDGF, TNF-alpha, and pi. Pflugers Archiv : Eur J Physiol. 2009;458(6):1151–61. doi:10.​1007/​s00424-009-0688-5.CrossRef
81.
82.
83.
84.
85.
86.
• Keasey MP, Lemos RR, Hagg T, Oliveira JR. Vitamin-D receptor agonist calcitriol reduces calcification in vitro through selective upregulation of SLC20A2 but not SLC20A1 or XPR1. Sci Rep. 2016;6:25802. doi:10.​1038/​srep25802. Incubation of calcifying SaOs2 cells with vitamin D increased SLC20A expression and maybe thereby reduced calcification.This in vitro study presents a new attractive option for treatment of IBGC PubMedPubMedCentralCrossRef
87.
88.
Eriksson M, Brown WT, Gordon LB, Glynn MW, Singer J, Scott L, et al. Recurrent de novo point mutations in lamin A cause Hutchinson-Gilford progeria syndrome. Nature. 2003;423(6937):293–8. doi:10.​1038/​nature01629.PubMedCrossRef
89.
Nair K, Ramachandran P, Krishnamoorthy KM, Dora S, Achuthan TJ. Hutchinson-Gilford progeria syndrome with severe calcific aortic valve stenosis and calcific mitral valve. J Heart Valve Dis. 2004;13(5):866–9.PubMed
90.
91.
92.
93.
94.
Nakano-Kurimoto R, Ikeda K, Uraoka M, Nakagawa Y, Yutaka K, Koide M, et al. Replicative senescence of vascular smooth muscle cells enhances the calcification through initiating the osteoblastic transition. Am J Physiol Heart Circ Physiol. 2009;297(5):H1673–84. doi:10.​1152/​ajpheart.​00455.​2009.PubMedCrossRef
95.
Liu Y, Drozdov I, Shroff R, Beltran LE, Shanahan CM. Prelamin A accelerates vascular calcification via activation of the DNA damage response and senescence-associated secretory phenotype in vascular smooth muscle cells. Circ Res. 2013;112(10):e99–109. doi:10.​1161/​CIRCRESAHA.​111.​300543.PubMedCrossRef
96.
•• Villa-Bellosta R, Rivera-Torres J, Osorio FG, Acin-Perez R, Enriquez JA, Lopez-Otin C, et al. Defective extracellular pyrophosphate metabolism promotes vascular calcification in a mouse model of Hutchinson-Gilford progeria syndrome that is ameliorated on pyrophosphate treatment. Circulation. 2013;127(24):2442–51. doi:10.​1161/​CIRCULATIONAHA.​112.​000571. This study for the first time directly links HGPS to disordered PP i metabolism. The authors successfully used PP i to prevent ectopic mineralization in HGPS animal model PubMedCrossRef
97.
Glynn MW, Glover TW. Incomplete processing of mutant lamin A in Hutchinson-Gilford progeria leads to nuclear abnormalities, which are reversed by farnesyltransferase inhibition. Hum Mol Genet. 2005;14(20):2959–69. doi:10.​1093/​hmg/​ddi326.PubMedCrossRef
98.
99.
100.
101.
•• Gordon LB, Kleinman ME, Massaro J, RB D’A Sr, Shappell H, Gerhard-Herman M, et al. Clinical trial of the protein farnesylation inhibitors lonafarnib, pravastatin, and zoledronic acid in children with Hutchinson-Gilford progeria syndrome. Circulation. 2016;134(2):114–25. doi:10.​1161/​CIRCULATIONAHA.​116.​022188. This study present data on a clinical trial on HGPS patient, treated with lonafarnib, pravastatin and zoledronate. The data impressively demonstrate the benefit of lonafarnib on cardiovascular calcification in HGPS patients, but clearify that addition of pravastatin and zoledronate have no added effect on arterial calcification PubMedPubMedCentralCrossRef
102.
Najjar SS, Farah FS, Kurban AK, Melhem RE, Khatchadourian AK. Tumoral calcinosis and pseudoxanthoma elasticum. J Pediatr. 1968;72(2):243–7.PubMedCrossRef
103.
Rafaelsen S, Johansson S, Raeder H, Bjerknes R. Long-term clinical outcome and phenotypic variability in hyperphosphatemic familial tumoral calcinosis and hyperphosphatemic hyperostosis syndrome caused by a novel GALNT3 mutation; case report and review of the literature. BMC Genet. 2014;15:98. doi:10.​1186/​s12863-014-0098-3.PubMedPubMedCentralCrossRef
104.
Shah A, Miller CJ, Nast CC, Adams MD, Truitt B, Tayek JA, et al. Severe vascular calcification and tumoral calcinosis in a family with hyperphosphatemia: a fibroblast growth factor 23 mutation identified by exome sequencing. Nephrol Dial Transplant Off Publ Eur Dial Transplant Assoc - Eur Ren Assoc. 2014;29(12):2235–43. doi:10.​1093/​ndt/​gfu324.CrossRef
105.
106.
107.
Topaz O, Shurman DL, Bergman R, Indelman M, Ratajczak P, Mizrachi M, et al. Mutations in GALNT3, encoding a protein involved in O-linked glycosylation, cause familial tumoral calcinosis. Nat Genet. 2004;36(6):579–81. doi:10.​1038/​ng1358.PubMedCrossRef
108.
109.
Kato K, Jeanneau C, Tarp MA, Benet-Pages A, Lorenz-Depiereux B, Bennett EP, et al. Polypeptide GalNAc-transferase T3 and familial tumoral calcinosis. Secretion of fibroblast growth factor 23 requires O-glycosylation. J Biol Chem. 2006;281(27):18370–7. doi:10.​1074/​jbc.​M602469200.PubMedCrossRef
110.
111.
112.
Kuro-o M, Matsumura Y, Aizawa H, Kawaguchi H, Suga T, Utsugi T, et al. Mutation of the mouse klotho gene leads to a syndrome resembling ageing. Nature. 1997;390(6655):45–51. doi:10.​1038/​36285.PubMedCrossRef
113.
114.
Yoshida T, Fujimori T, Nabeshima Y. Mediation of unusually high concentrations of 1,25-dihydroxyvitamin D in homozygous klotho mutant mice by increased expression of renal 1alpha-hydroxylase gene. Endocrinology. 2002;143(2):683–9. doi:10.​1210/​endo.​143.​2.​8657.PubMedCrossRef
115.
Shimada T, Kakitani M, Yamazaki Y, Hasegawa H, Takeuchi Y, Fujita T, et al. Targeted ablation of Fgf23 demonstrates an essential physiological role of FGF23 in phosphate and vitamin D metabolism. J Clin Invest. 2004;113(4):561–8. doi:10.​1172/​JCI19081.PubMedPubMedCentralCrossRef
116.
117.
118.
119.
Lammoglia JJ, Mericq V. Familial tumoral calcinosis caused by a novel FGF23 mutation: response to induction of tubular renal acidosis with acetazolamide and the non-calcium phosphate binder sevelamer. Horm Res. 2009;71(3):178–84. doi:10.​1159/​000197876.PubMedCrossRef
120.
•• Chen TH, Kuro OM, Chen CH, Sue YM, Chen YC, Wu HH, et al. The secreted klotho protein restores phosphate retention and suppresses accelerated aging in klotho mutant mice. Eur J Pharmacol. 2013;698(1–3):67–73. doi:10.​1016/​j.​ejphar.​2012.​09.​032. In this study, recombinant soluble Klotho protein successfully prevents ectopic calcification and accelerated aging in Klotho deficient mice PubMedCrossRef
121.
•• Hum JM, O, Bryan LM, Tatiparthi AK, Cass TA, Clinkenbeard EL, Cramer MS, et al. Chronic hyperphosphatemia and vascular calcification are reduced by stable delivery of soluble klotho. J Am Soc Nephrol JASN. 2016; doi:10.​1681/​ASN.​2015111266. In this study, stable delivery of adeno-associated virus expressing soluble Klotho protein successfully prevents aortic calcification in Klotho deficient mice PubMedPubMedCentralCrossRef
122.
Leibrock CB, Feger M, Voelkl J, Kohlhofer U, Quintanilla-Martinez L, Kuro-o M, et al. Partial reversal of tissue calcification and extension of life span following ammonium nitrate treatment of klotho-deficient mice. Kidney Blood Press Res. 2016;41(1):99–107. doi:10.​1159/​000443411.PubMedCrossRef
123.
124.
125.
•• Leibrock CB, Alesutan I, Voelkl J, Michael D, Castor T, Kohlhofer U, et al. Acetazolamide sensitive tissue calcification and aging of klotho-hypomorphic mice. J Mol Med. 2016;94(1):95–106. doi:10.​1007/​s00109-015-1331-x. The study revealed a powerful effect of acetazolamide on arterial calcification, including osteoinductive signaling, in Klotho deficient mice PubMedCrossRef
126.
•• Jost J, Bahans C, Courbebaisse M, Tran TA, Linglart A, Benistan K, et al. Topical sodium thiosulfate: a treatment for calcifications in hyperphosphatemic familial tumoral calcinosis? J Clin Endocrinol Metab. 2016;101(7):2810–5. doi:10.​1210/​jc.​2016-1087. The authors presented an interesting study on a very effective topical treatment of ectopic calcification in HFTC with sodium thiosulfate PubMedCrossRef
127.
128.
Adirekkiat S, Sumethkul V, Ingsathit A, Domrongkitchaiporn S, Phakdeekitcharoen B, Kantachuvesiri S, et al. Sodium thiosulfate delays the progression of coronary artery calcification in haemodialysis patients. Nephrol Dial Transplant Off Publ Eur Dial Transplant Assoc - Eur Ren Assoc. 2010;25(6):1923–9. doi:10.​1093/​ndt/​gfp755.CrossRef
129.
130.
Hall MC, Matson SW. Helicase motifs: the engine that powers DNA unwinding. Mol Microbiol. 1999;34(5):867–77.PubMedCrossRef
131.
•• Funabiki M, Kato H, Miyachi Y, Toki H, Motegi H, Inoue M, et al. Autoimmune disorders associated with gain of function of the intracellular sensor MDA5. Immunity. 2014;40(2):199–212. doi:10.​1016/​j.​immuni.​2013.​12.​014. In this elegant study, the authors show how a gain of function mutation in MDA5, an intracellular receptor for viral RNA through elevated type I interferon signaling leads to a lupus-like phenotype including ectopic calcifications in an animal model PubMedCrossRef
132.
Rice GI, del Toro DY, Jenkinson EM, Forte GM, Anderson BH, Ariaudo G, et al. Gain-of-function mutations in IFIH1 cause a spectrum of human disease phenotypes associated with upregulated type I interferon signaling. Nat Genet. 2014;46(5):503–9. doi:10.​1038/​ng.​2933.PubMedPubMedCentralCrossRef
133.
Bursztejn AC, Briggs TA, del Toro Duany Y, Anderson BH, O’Sullivan J, Williams SG, et al. Unusual cutaneous features associated with a heterozygous gain-of-function mutation in IFIH1: overlap between Aicardi-Goutieres and Singleton-Merten syndromes. Br J Dermatol. 2015;173(6):1505–13. doi:10.​1111/​bjd.​14073.PubMedPubMedCentralCrossRef
134.
•• Jang MA, Kim EK, Now H, Nguyen NT, Kim WJ, Yoo JY, et al. Mutations in DDX58, which encodes RIG-I, cause atypical Singleton-Merten syndrome. Am J Hum Genet. 2015;96(2):266–74. doi:10.​1016/​j.​ajhg.​2014.​11.​019. Here, the authors for the first time provide a link of a familiar syndrome consisting of glaucoma, aortic calcification and skeletal abnormalities to gain of function mutations in DDX58 encoding RIG-I, an intracellular receptor for double stranded RNA PubMedPubMedCentralCrossRef
135.
Lassig C, Matheisl S, Sparrer KM, de Oliveira Mann CC, Moldt M, Patel JR et al. ATP hydrolysis by the viral RNA sensor RIG-I prevents unintentional recognition of self-RNA. eLife. 2015;4. doi:10.​7554/​eLife.​10859.
136.
137.
138.
Munroe PB, Olgunturk RO, Fryns JP, Van Maldergem L, Ziereisen F, Yuksel B, et al. Mutations in the gene encoding the human matrix Gla protein cause Keutel syndrome. Nat Genet. 1999;21(1):142–4. doi:10.​1038/​5102.PubMedCrossRef
139.
Meier M, Weng LP, Alexandrakis E, Ruschoff J, Goeckenjan G. Tracheobronchial stenosis in Keutel syndrome. Eur Respir J. 2001;17(3):566–9.PubMedCrossRef
140.
141.
El-Maadawy S, Kaartinen MT, Schinke T, Murshed M, Karsenty G, McKee MD. Cartilage formation and calcification in arteries of mice lacking matrix Gla protein. Connect Tissue Res. 2003;44(Suppl 1):272–8.PubMedCrossRef
142.
Luo G, Ducy P, McKee MD, Pinero GJ, Loyer E, Behringer RR, et al. Spontaneous calcification of arteries and cartilage in mice lacking matrix GLA protein. Nature. 1997;386(6620):78–81. doi:10.​1038/​386078a0.PubMedCrossRef
143.
144.
145.
Leroux-Berger M, Queguiner I, Maciel TT, Ho A, Relaix F, Kempf H. Pathologic calcification of adult vascular smooth muscle cells differs on their crest or mesodermal embryonic origin. J Bone Miner Res Off J Am Soc Bone Miner Res. 2011;26(7):1543–53. doi:10.​1002/​jbmr.​382.CrossRef
146.
• Beazley KE, Reckard S, Nurminsky D, Lima F, Nurminskaya M. Two sides of MGP null arterial disease: chondrogenic lesions dependent on transglutaminase 2 and elastin fragmentation associated with induction of adipsin. J Biol Chem. 2013;288(43):31400–8. doi:10.​1074/​jbc.​M113.​495556. This paper demonstrates, that arterial calcification in MGP deficient mice is more than ectopic chondrogenesis. First elastin fragmentation takes place, which already enables calcification, and vascular SMC pass through chondrogenic transdifferentiation leading to formation of cartilaginous lesions in the arteries PubMedPubMedCentralCrossRef
147.
Khavandgar Z, Roman H, Li J, Lee S, Vali H, Brinckmann J, et al. Elastin haploinsufficiency impedes the progression of arterial calcification in MGP-deficient mice. J Bone Miner Res Off J Am Soc Bone Miner Res. 2014;29(2):327–37. doi:10.​1002/​jbmr.​2039.CrossRef
148.
Price PA, Faus SA, Williamson MK. Warfarin causes rapid calcification of the elastic lamellae in rat arteries and heart valves. Arterioscler Thromb Vasc Biol. 1998;18(9):1400–7.PubMedCrossRef
149.
•• Cranenburg EC, VANS-Z KY, Bonafe L, Mittaz Crettol L, Rodiger LA, Dikkers FG, et al. Circulating matrix gamma-carboxyglutamate protein (MGP) species are refractory to vitamin K treatment in a new case of Keutel syndrome. J Thromb Haemost JTH. 2011;9(6):1225–35. doi:10.​1111/​j.​1538-7836.​2011.​04263.​x. Very interesting case report, presenting a Keutel patient with uncarboxylated, but phosphorylated MGP, which is not sensitive to vitamin K. The authors speculate, that this phosphorylated MGP still has residual protein function and thereby prevented calcification in this patient PubMedCrossRef
150.
151.
152.
Schiffmann R, Heyes MP, Aerts JM, Dambrosia JM, Patterson MC, DeGraba T, et al. Prospective study of neurological responses to treatment with macrophage-targeted glucocerebrosidase in patients with type 3 Gaucher’s disease. Ann Neurol. 1997;42(4):613–21. doi:10.​1002/​ana.​410420412.PubMedCrossRef
153.
Bohlega S, Kambouris M, Shahid M, Al Homsi M, Al Sous W. Gaucher disease with oculomotor apraxia and cardiovascular calcification (Gaucher type IIIC). Neurology. 2000;54(1):261–3.PubMedCrossRef
154.
George R, McMahon J, Lytle B, Clark B, Lichtin A. Severe valvular and aortic arch calcification in a patient with Gaucher’s disease homozygous for the D409H mutation. Clin Genet. 2001;59(5):360–3.PubMedCrossRef
155.
El-Beshlawy A, Tylki-Szymanska A, Vellodi A, Belmatoug N, Grabowski GA, Kolodny EH, et al. Long-term hematological, visceral, and growth outcomes in children with Gaucher disease type 3 treated with imiglucerase in the International Collaborative Gaucher Group Gaucher Registry. Mol Genet Metab. 2017;120(1–2):47–56. doi:10.​1016/​j.​ymgme.​2016.​12.​001.PubMedCrossRef
156.
Metadata
Title
Inherited Arterial Calcification Syndromes: Etiologies and Treatment Concepts
Authors
Yvonne Nitschke
Frank Rutsch
Publication date
01-08-2017
Publisher
Springer US
Published in
Current Osteoporosis Reports / Issue 4/2017
Print ISSN: 1544-1873
Electronic ISSN: 1544-2241
DOI
https://doi.org/10.1007/s11914-017-0370-3

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