{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,23]],"date-time":"2026-08-23T18:19:54Z","timestamp":1787509194595,"version":"build-2736575974"},"reference-count":29,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2022,11,18]],"date-time":"2022-11-18T00:00:00Z","timestamp":1668729600000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2022,11,18]],"date-time":"2022-11-18T00:00:00Z","timestamp":1668729600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"name":"Daiichi Sankyo, Inc."}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Sci Rep"],"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>\n                    Pseudoxanthoma elasticum (PXE) is a multisystem, genetic, ectopic mineralization disorder with no effective treatment. Inhibition of tissue-nonspecific alkaline phosphatase (TNAP) may prevent ectopic soft tissue calcification by increasing endogenous pyrophosphate (PPi). This study evaluated the anticalcification effects of DS-1211, an orally administered, potent, and highly selective small molecule TNAP inhibitor, in mouse models of PXE. Calcium content in vibrissae was measured in KK\/HlJ and\n                    <jats:italic>ABCC6<\/jats:italic>\n                    <jats:sup>\n                      <jats:italic>-\/-<\/jats:italic>\n                    <\/jats:sup>\n                    mice after DS-1211 administration for 13\u201314\u00a0weeks. Pharmacokinetic and pharmacodynamic effects of DS-1211 were evaluated, including plasma alkaline phosphatase (ALP) activity and biomarker changes in PPi and pyridoxal-phosphate (PLP). Anticalcification effects of DS-1211 through TNAP inhibition were further evaluated in\n                    <jats:italic>ABCC6<\/jats:italic>\n                    <jats:sup>\n                      <jats:italic>-\/-<\/jats:italic>\n                    <\/jats:sup>\n                    mice with genetically reduced TNAP activity,\n                    <jats:italic>ABCC6<\/jats:italic>\n                    <jats:sup>\n                      <jats:italic>-\/-<\/jats:italic>\n                    <\/jats:sup>\n                    \/TNAP\n                    <jats:sup>+\/+<\/jats:sup>\n                    and\n                    <jats:italic>ABCC6<\/jats:italic>\n                    <jats:sup>\n                      <jats:italic>-\/-<\/jats:italic>\n                    <\/jats:sup>\n                    \/TNAP\n                    <jats:sup>+\/-<\/jats:sup>\n                    . In KK\/HlJ and\n                    <jats:italic>ABCC6<\/jats:italic>\n                    <jats:sup>\n                      <jats:italic>-\/-<\/jats:italic>\n                    <\/jats:sup>\n                    mouse models, DS-1211 inhibited plasma ALP activity in a dose-dependent manner and prevented progression of ectopic calcification compared with vehicle-treated mice. Plasma PPi and PLP increased dose-dependently with DS-1211 in\n                    <jats:italic>ABCC6<\/jats:italic>\n                    <jats:sup>\n                      <jats:italic>-\/-<\/jats:italic>\n                    <\/jats:sup>\n                    mice. Mice with\n                    <jats:italic>ABCC6<\/jats:italic>\n                    <jats:sup>\n                      <jats:italic>-\/-<\/jats:italic>\n                    <\/jats:sup>\n                    \/TNAP\n                    <jats:sup>+\/-<\/jats:sup>\n                    phenotype had significantly less calcification and higher plasma PPi and PLP than\n                    <jats:italic>ABCC6<\/jats:italic>\n                    <jats:sup>\n                      <jats:italic>-\/-<\/jats:italic>\n                    <\/jats:sup>\n                    \/TNAP\n                    <jats:sup>+\/+<\/jats:sup>\n                    mice. TNAP plays an active role in pathomechanistic pathways of dysregulated calcification, demonstrated by reduced ectopic calcification in mice with lower TNAP activity. DS-1211 may be a potential therapeutic drug for PXE.\n                  <\/jats:p>","DOI":"10.1038\/s41598-022-23892-5","type":"journal-article","created":{"date-parts":[[2022,11,18]],"date-time":"2022-11-18T10:04:10Z","timestamp":1668765850000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Anticalcification effects of DS-1211 in pseudoxanthoma elasticum mouse models and the role of tissue-nonspecific alkaline phosphatase in ABCC6-deficient ectopic calcification"],"prefix":"10.1038","volume":"12","author":[{"given":"Kaori","family":"Soma","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kengo","family":"Watanabe","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Masanori","family":"Izumi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2022,11,18]]},"reference":[{"key":"23892_CR1","doi-asserted-by":"publisher","first-page":"671","DOI":"10.1016\/s0002-9440(10)65313-8","volume":"154","author":"CM Giachelli","year":"1999","unstructured":"Giachelli, C. M. Ectopic calcification: Gathering hard facts about soft tissue mineralization. Am. J. Pathol. 154, 671\u2013675. https:\/\/doi.org\/10.1016\/s0002-9440(10)65313-8 (1999).","journal-title":"Am. J. Pathol."},{"key":"23892_CR2","doi-asserted-by":"publisher","first-page":"360","DOI":"10.1016\/j.jid.2018.07.030","volume":"139","author":"Q Li","year":"2019","unstructured":"Li, Q. et al. Inhibition of tissue-nonspecific alkaline phosphatase attenuates ectopic mineralization in the Abcc6(-\/-) mouse model of PXE but not in the Enpp1 mutant mouse models of GACI. J. Invest. Dermatol. 139, 360\u2013368. https:\/\/doi.org\/10.1016\/j.jid.2018.07.030 (2019).","journal-title":"J. Invest. Dermatol."},{"key":"23892_CR3","doi-asserted-by":"publisher","first-page":"2012","DOI":"10.6064\/2012\/598262","volume":"598262","author":"MJ Hosen","year":"2012","unstructured":"Hosen, M. J., Lamoen, A., De Paepe, A. & Vanakker, O. M. Histopathology of pseudoxanthoma elasticum and related disorders: Histological hallmarks and diagnostic clues. Scientifica (Cairo). 598262, 2012. https:\/\/doi.org\/10.6064\/2012\/598262 (2012).","journal-title":"Scientifica (Cairo)."},{"key":"23892_CR4","doi-asserted-by":"publisher","first-page":"85","DOI":"10.1186\/s13023-017-0639-8","volume":"12","author":"DP Germain","year":"2017","unstructured":"Germain, D. P. Pseudoxanthoma elasticum. Orphanet J. Rare Dis. 12, 85. https:\/\/doi.org\/10.1186\/s13023-017-0639-8 (2017).","journal-title":"Orphanet J. Rare Dis."},{"key":"23892_CR5","doi-asserted-by":"publisher","first-page":"790","DOI":"10.1016\/j.jid.2016.12.014","volume":"137","author":"J Uitto","year":"2017","unstructured":"Uitto, J., Li, Q., van de Wetering, K., V\u00e1radi, A. & Terry, S. F. Insights into pathomechanisms and treatment development in heritable ectopic mineralization disorders: Summary of the PXE international biennial research symposium-2016. J. Investig. Dermatol. 137, 790\u2013795. https:\/\/doi.org\/10.1016\/j.jid.2016.12.014 (2017).","journal-title":"J. Investig. Dermatol."},{"key":"23892_CR6","doi-asserted-by":"publisher","first-page":"20206","DOI":"10.1073\/pnas.1319582110","volume":"110","author":"RS Jansen","year":"2013","unstructured":"Jansen, R. S. et al. ABCC6 prevents ectopic mineralization seen in pseudoxanthoma elasticum by inducing cellular nucleotide release. Proc. Natl. Acad. Sci. USA 110, 20206\u201320211. https:\/\/doi.org\/10.1073\/pnas.1319582110 (2013).","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"23892_CR7","doi-asserted-by":"publisher","first-page":"1258","DOI":"10.1016\/j.ajpath.2017.02.009","volume":"187","author":"V Pomozi","year":"2017","unstructured":"Pomozi, V. et al. Pyrophosphate supplementation prevents chronic and acute calcification in ABCC6-deficient mice. Am. J. Pathol. 187, 1258\u20131272. https:\/\/doi.org\/10.1016\/j.ajpath.2017.02.009 (2017).","journal-title":"Am. J. Pathol."},{"key":"23892_CR8","doi-asserted-by":"publisher","first-page":"1463","DOI":"10.15252\/emmm.201707532","volume":"9","author":"D Dedinszki","year":"2017","unstructured":"Dedinszki, D. et al. Oral administration of pyrophosphate inhibits connective tissue calcification. EMBO Mol. Med. 9, 1463\u20131470. https:\/\/doi.org\/10.15252\/emmm.201707532 (2017).","journal-title":"EMBO Mol. Med."},{"key":"23892_CR9","doi-asserted-by":"publisher","first-page":"14","DOI":"10.1016\/j.coph.2016.02.002","volume":"28","author":"NA Rashdan","year":"2016","unstructured":"Rashdan, N. A. et al. New perspectives on rare connective tissue calcifying diseases. Curr. Opin. Pharmacol. 28, 14\u201323. https:\/\/doi.org\/10.1016\/j.coph.2016.02.002 (2016).","journal-title":"Curr. Opin. Pharmacol."},{"key":"23892_CR10","doi-asserted-by":"publisher","first-page":"31","DOI":"10.1016\/j.bmcl.2017.11.024","volume":"28","author":"AB Pinkerton","year":"2018","unstructured":"Pinkerton, A. B. et al. Discovery of 5-((5-chloro-2-methoxyphenyl)sulfonamido)nicotinamide (SBI-425), a potent and orally bioavailable tissue-nonspecific alkaline phosphatase (TNAP) inhibitor. Bioorg. Med. Chem. Lett. 28, 31\u201334. https:\/\/doi.org\/10.1016\/j.bmcl.2017.11.024 (2018).","journal-title":"Bioorg. Med. Chem. Lett."},{"key":"23892_CR11","doi-asserted-by":"publisher","first-page":"9445","DOI":"10.1073\/pnas.142063399","volume":"99","author":"L Hessle","year":"2002","unstructured":"Hessle, L. et al. Tissue-nonspecific alkaline phosphatase and plasma cell membrane glycoprotein-1 are central antagonistic regulators of bone mineralization. Proc. Natl. Acad. Sci. USA 99, 9445\u20139449. https:\/\/doi.org\/10.1073\/pnas.142063399 (2002).","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"23892_CR12","doi-asserted-by":"publisher","first-page":"961","DOI":"10.1172\/JCI106589","volume":"50","author":"RG Russell","year":"1971","unstructured":"Russell, R. 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. Investig. 50, 961\u2013969. https:\/\/doi.org\/10.1172\/JCI106589 (1971).","journal-title":"J. Clin. Investig."},{"key":"23892_CR13","doi-asserted-by":"publisher","first-page":"752","DOI":"10.1172\/jci112031","volume":"76","author":"MP Whyte","year":"1985","unstructured":"Whyte, M. P., Mahuren, J. D., Vrabel, L. A. & Coburn, S. P. Markedly increased circulating pyridoxal-5\u2019-phosphate levels in hypophosphatasia. Alkaline phosphatase acts in vitamin B6 metabolism. J. Clin. Investig. 76, 752\u2013756. https:\/\/doi.org\/10.1172\/jci112031 (1985).","journal-title":"J. Clin. Investig."},{"key":"23892_CR14","doi-asserted-by":"publisher","first-page":"1440","DOI":"10.1172\/JCI117814","volume":"95","author":"MP Whyte","year":"1995","unstructured":"Whyte, M. P. et al. Alkaline phosphatase: Placental and tissue-nonspecific isoenzymes hydrolyze phosphoethanolamine, inorganic pyrophosphate, and pyridoxal 5\u2019-phosphate. Substrate accumulation in carriers of hypophosphatasia corrects during pregnancy. J. Clin. Investig. 95, 1440\u20131445 (1995).","journal-title":"J. Clin. Investig."},{"key":"23892_CR15","doi-asserted-by":"publisher","first-page":"1862","DOI":"10.1359\/jbmr.040608","volume":"19","author":"A Kozlenkov","year":"2004","unstructured":"Kozlenkov, A. et al. Residues determining the binding specificity of uncompetitive inhibitors to tissue-nonspecific alkaline phosphatase. J. Bone Miner. Res. 19, 1862\u20131872. https:\/\/doi.org\/10.1359\/jbmr.040608 (2004).","journal-title":"J. Bone Miner. Res."},{"key":"23892_CR16","doi-asserted-by":"publisher","first-page":"1700","DOI":"10.1359\/jbmr.070714","volume":"22","author":"S Narisawa","year":"2007","unstructured":"Narisawa, S. et al. Novel inhibitors of alkaline phosphatase suppress vascular smooth muscle cell calcification. J. Bone Miner. Res. 22, 1700\u20131710. https:\/\/doi.org\/10.1359\/jbmr.070714 (2007).","journal-title":"J. Bone Miner. Res."},{"key":"23892_CR17","doi-asserted-by":"publisher","first-page":"eaal669","DOI":"10.1126\/scitranslmed.aal1669","volume":"9","author":"SG Ziegler","year":"2017","unstructured":"Ziegler, S. G. et al. Ectopic calcification in pseudoxanthoma elasticum responds to inhibition of tissue-nonspecific alkaline phosphatase. Sci. Transl. Med. 9, eaal669. https:\/\/doi.org\/10.1126\/scitranslmed.aal1669 (2017).","journal-title":"Sci. Transl. Med."},{"key":"23892_CR18","doi-asserted-by":"publisher","first-page":"1190","DOI":"10.1016\/j.ajpath.2012.06.014","volume":"181","author":"Q Li","year":"2012","unstructured":"Li, Q., Berndt, A., Guo, H., Sundberg, J. P. & Uitto, J. A novel animal model for pseudoxanthoma elasticum: The KK\/HlJ mouse. Am. J. Pathol. 181, 1190\u20131196. https:\/\/doi.org\/10.1016\/j.ajpath.2012.06.014 (2012).","journal-title":"Am. J. Pathol."},{"key":"23892_CR19","doi-asserted-by":"publisher","first-page":"1025","DOI":"10.1016\/j.jid.2016.11.042","volume":"137","author":"Q Li","year":"2017","unstructured":"Li, Q. et al. Abcc6 knockout rat model highlights the role of liver in PPi Homeostasis in pseudoxanthoma elasticum. J. Investig. Dermatol. 137, 1025\u20131032. https:\/\/doi.org\/10.1016\/j.jid.2016.11.042 (2017).","journal-title":"J. Investig. Dermatol."},{"key":"23892_CR20","doi-asserted-by":"publisher","first-page":"8299","DOI":"10.1128\/mcb.25.18.8299-8310.2005","volume":"25","author":"JF Klement","year":"2005","unstructured":"Klement, J. F. et al. Targeted ablation of the abcc6 gene results in ectopic mineralization of connective tissues. Mol. Cell Biol. 25, 8299\u20138310. https:\/\/doi.org\/10.1128\/mcb.25.18.8299-8310.2005 (2005).","journal-title":"Mol. Cell Biol."},{"key":"23892_CR21","doi-asserted-by":"publisher","DOI":"10.1002\/jbmr.4680","author":"K Soma","year":"2022","unstructured":"Soma, K., Izumi, M., Yamamoto, Y., Miyazaki, S. & Watanabe, K. In vitro and in vivo pharmacological profiles of DS-1211, a novel potent, selective, and orally bioavailable tissue-nonspecific alkaline phosphatase inhibitor. J. Bone Miner. Res. https:\/\/doi.org\/10.1002\/jbmr.4680 (2022).","journal-title":"J. Bone Miner. Res."},{"key":"23892_CR22","doi-asserted-by":"publisher","DOI":"10.1111\/cts.13214","author":"S Maruyama","year":"2022","unstructured":"Maruyama, S. et al. Phase I studies of the safety, tolerability, pharmacokinetics, and pharmacodynamics of DS-1211, a tissue-nonspecific alkaline phosphatase inhibitor. Clin. Transl. Sci. https:\/\/doi.org\/10.1111\/cts.13214 (2022).","journal-title":"Clin. Transl. Sci."},{"key":"23892_CR23","doi-asserted-by":"publisher","first-page":"7179","DOI":"10.3402\/pba.v1i0.7179","volume":"1","author":"JP Sundberg","year":"2011","unstructured":"Sundberg, J. P. et al. The mouse as a model for understanding chronic diseases of aging: The histopathologic basis of aging in inbred mice. Pathobiol. Aging Age Relat. Dis. 1, 7179. https:\/\/doi.org\/10.3402\/pba.v1i0.7179 (2011).","journal-title":"Pathobiol. Aging Age Relat. Dis."},{"key":"23892_CR24","doi-asserted-by":"publisher","first-page":"3611","DOI":"10.1111\/bph.15178","volume":"177","author":"E Lilley","year":"2020","unstructured":"Lilley, E. et al. ARRIVE 2.0 and the British journal of pharmacology: Updated guidance for 2020. Br. J. Pharmacol. 177, 3611\u20133616. https:\/\/doi.org\/10.1111\/bph.15178 (2020).","journal-title":"Br. J. Pharmacol."},{"key":"23892_CR25","doi-asserted-by":"publisher","first-page":"173","DOI":"10.1007\/s00109-009-0522-8","volume":"88","author":"Q Li","year":"2010","unstructured":"Li, Q. & Uitto, J. The mineralization phenotype in Abcc6 ( -\/- ) mice is affected by Ggcx gene deficiency and genetic background\u2013a model for pseudoxanthoma elasticum. J. Mol. Med. (Berl). 88, 173\u2013181. https:\/\/doi.org\/10.1007\/s00109-009-0522-8 (2010).","journal-title":"J. Mol. Med. (Berl)."},{"key":"23892_CR26","doi-asserted-by":"publisher","first-page":"446","DOI":"10.1007\/bf00157809","volume":"25","author":"J Rungby","year":"1993","unstructured":"Rungby, J., Kassem, M., Eriksen, E. F. & Danscher, G. The von Kossa reaction for calcium deposits: Silver lactate staining increases sensitivity and reduces background. Histochem. J. 25, 446\u2013451. https:\/\/doi.org\/10.1007\/bf00157809 (1993).","journal-title":"Histochem. J."},{"key":"23892_CR27","doi-asserted-by":"publisher","first-page":"191","DOI":"10.6065\/apem.2013.18.4.191","volume":"18","author":"HJ Jwa","year":"2013","unstructured":"Jwa, H. J., Yang, S. I. & Lim, H. H. The difference in serum alkaline phosphatase levels between girls with precocious puberty and those with normal puberty. Ann. Pediatr. Endocrinol. Metab. 18, 191\u2013195. https:\/\/doi.org\/10.6065\/apem.2013.18.4.191 (2013).","journal-title":"Ann. Pediatr. Endocrinol. Metab."},{"key":"23892_CR28","doi-asserted-by":"publisher","first-page":"1763","DOI":"10.1093\/hmg\/ddi183","volume":"14","author":"TG Gorgels","year":"2005","unstructured":"Gorgels, T. G. et al. Disruption of Abcc6 in the mouse: Novel insight in the pathogenesis of pseudoxanthoma elasticum. Hum. Mol. Genet. 14, 1763\u20131773. https:\/\/doi.org\/10.1093\/hmg\/ddi183 (2005).","journal-title":"Hum. Mol. Genet."},{"key":"23892_CR29","doi-asserted-by":"publisher","first-page":"398","DOI":"10.1007\/s00223-015-0079-1","volume":"98","author":"JL Mill\u00e1n","year":"2016","unstructured":"Mill\u00e1n, J. L. & Whyte, M. P. Alkaline phosphatase and hypophosphatasia. Calcif. Tissue Int. 98, 398\u2013416. https:\/\/doi.org\/10.1007\/s00223-015-0079-1 (2016).","journal-title":"Calcif. Tissue Int."}],"container-title":["Scientific Reports"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41598-022-23892-5.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-022-23892-5","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-022-23892-5.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,11,18]],"date-time":"2022-11-18T10:16:23Z","timestamp":1668766583000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41598-022-23892-5"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,11,18]]},"references-count":29,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2022,12]]}},"alternative-id":["23892"],"URL":"https:\/\/doi.org\/10.1038\/s41598-022-23892-5","relation":{},"ISSN":["2045-2322"],"issn-type":[{"value":"2045-2322","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,11,18]]},"assertion":[{"value":"9 March 2022","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"7 November 2022","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"18 November 2022","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"All authors are employees of Daiichi Sankyo.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"19852"}}