{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,23]],"date-time":"2026-08-23T17:20:28Z","timestamp":1787505628264,"version":"build-2736575974"},"reference-count":28,"publisher":"MDPI AG","issue":"20","license":[{"start":{"date-parts":[[2023,10,10]],"date-time":"2023-10-10T00:00:00Z","timestamp":1696896000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"PXE International","award":["R21AR077332"],"award-info":[{"award-number":["R21AR077332"]}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health\/National Institute of Arthritis and Musculoskeletal and Skin Diseases","doi-asserted-by":"publisher","award":["R21AR077332"],"award-info":[{"award-number":["R21AR077332"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Pseudoxanthoma elasticum (PXE) is a heritable multisystem ectopic calcification disorder. The gene responsible for PXE, ABCC6, encodes ABCC6, a hepatic efflux transporter regulating extracellular inorganic pyrophosphate (PPi), a potent endogenous calcification inhibitor. Recent studies demonstrated that in addition to the deficiency of plasma PPi, the activated DDR\/PARP signaling in calcified tissues provides an additional possible mechanism of ectopic calcification in PXE. This study examined the effects of etidronate (ETD), a stable PPi analog, and its combination with minocycline (Mino), a potent inhibitor of DDR\/PARP, on ectopic calcification in an Abcc6-\/- mouse model of PXE. Abcc6-\/- mice, at 4 weeks of age, before the development of ectopic calcification, were treated with ETD, Mino, or both for 18 weeks. Micro-computed tomography, histopathologic examination, and quantification of the calcium content in Abcc6-\/- mice treated with both ETD and Mino revealed further reduced calcification than either treatment alone. The effects were associated with reduced serum alkaline phosphatase activity without changes in plasma PPi concentrations. These results suggest that ETD and Mino combination therapy might provide an effective therapeutic approach for PXE, a currently intractable disease.<\/jats:p>","DOI":"10.3390\/ijms242015041","type":"journal-article","created":{"date-parts":[[2023,10,10]],"date-time":"2023-10-10T06:14:04Z","timestamp":1696918444000},"page":"15041","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Novel Treatments for PXE: Targeting the Systemic and Local Drivers of Ectopic Calcification"],"prefix":"10.3390","volume":"24","author":[{"given":"Ida Joely","family":"Jacobs","sequence":"first","affiliation":[{"name":"Biomedical Sciences MS Program, Jefferson College of Life Sciences, Thomas Jefferson University, Philadelphia, PA 19107, USA"},{"name":"Department of Biochemistry and Molecular Biology, Thomas Jefferson University, Philadelphia, PA 19107, USA"},{"name":"PXE International Center of Excellence in Research and Clinical Care, Thomas Jefferson University, Philadelphia, PA 19107, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8495-7103","authenticated-orcid":false,"given":"Qiaoli","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biology, Thomas Jefferson University, Philadelphia, PA 19107, USA"},{"name":"PXE International Center of Excellence in Research and Clinical Care, Thomas Jefferson University, Philadelphia, PA 19107, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,10,10]]},"reference":[{"key":"ref_1","first-page":"1","article-title":"Pseudoxanthoma elasticum","volume":"6","author":"Neldner","year":"1988","journal-title":"Clin. Dermatol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"113","DOI":"10.5582\/irdr.2015.01014","article-title":"Pseudoxanthoma elasticum and skin: Clinical manifestations, histopathology, pathomechanism, perspectives of treatment","volume":"4","author":"Marconi","year":"2015","journal-title":"Intractable Rare Dis. Res."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"228","DOI":"10.1038\/76109","article-title":"Mutations in ABCC6 cause pseudoxanthoma elasticum","volume":"25","author":"Bergen","year":"2000","journal-title":"Nat. Genet."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"223","DOI":"10.1038\/76102","article-title":"Mutations in a gene encoding an ABC transporter cause pseudoxanthoma elasticum","volume":"25","author":"Urban","year":"2000","journal-title":"Nat. Genet."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"6001","DOI":"10.1073\/pnas.100041297","article-title":"Pseudoxanthoma elasticum: Mutations in the MRP6 gene encoding a transmembrane ATP-binding cassette (ABC) transporter","volume":"97","author":"Ringpfeil","year":"2000","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"2193","DOI":"10.1002\/jbmr.4418","article-title":"Ectopic calcification and hypophosphatemic rickets: Natural history of ENPP1 and ABCC6 deficiencies","volume":"36","author":"Ferreira","year":"2021","journal-title":"J. Bone Miner. Res."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"25","DOI":"10.1016\/j.ajhg.2011.11.020","article-title":"Generalized arterial calcification of infancy and pseudoxanthoma elasticum can be caused by mutations in either ENPP1 or ABCC6","volume":"90","author":"Nitschke","year":"2012","journal-title":"Am. J. Hum. Genet."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1985","DOI":"10.1161\/ATVBAHA.114.304017","article-title":"ABCC6-mediated ATP secretion by the liver is the main source of the mineralization inhibitor inorganic pyrophosphate in the systemic circulation\u2014Brief report","volume":"34","author":"Jansen","year":"2014","journal-title":"Arterioscler. Thromb. Vasc. Biol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"20206","DOI":"10.1073\/pnas.1319582110","article-title":"ABCC6 prevents ectopic mineralization seen in pseudoxanthoma elasticum by inducing cellular nucleotide release","volume":"110","author":"Jansen","year":"2013","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1024","DOI":"10.1002\/jbmr.4528","article-title":"The Mineralization Regulator ANKH Mediates Cellular Efflux of ATP, Not Pyrophosphate","volume":"37","author":"Szeri","year":"2022","journal-title":"J. Bone Min. Res."},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Szeri, F., Lundkvist, S., Donnelly, S., Engelke, U.F.H., Rhee, K., Williams, C.J., Sundberg, J.P., Wevers, R.A., Tomlinson, R.E., and Jansen, R.S. (2020). The membrane protein ANKH is crucial for bone mechanical performance by mediating cellular export of citrate and ATP. PLoS Genet., 16.","DOI":"10.1371\/journal.pgen.1008884"},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"Shimada, B.K., Pomozi, V., Zoll, J., Kuo, S., Martin, L., and Le Saux, O. (2021). ABCC6, pyrophosphate and ectopic calcification: Therapeutic solutions. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms22094555"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"457","DOI":"10.1002\/jbmr.4791","article-title":"Weighing the Evidence for the Roles of Plasma Versus Local Pyrophosphate in Ectopic Calcification Disorders","volume":"38","author":"Ralph","year":"2023","journal-title":"J. Bone Min. Res."},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Luo, H., Li, Q., Cao, Y., and Uitto, J. (2020). Therapeutics Development for Pseudoxanthoma Elasticum and Related Ectopic Mineralization Disorders: Update 2020. J. Clin. Med., 10.","DOI":"10.3390\/jcm10010114"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1463","DOI":"10.15252\/emmm.201707532","article-title":"Oral administration of pyrophosphate inhibits connective tissue calcification","volume":"9","author":"Dedinszki","year":"2017","journal-title":"EMBO Mol. Med."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1082","DOI":"10.1080\/15384101.2015.1007809","article-title":"The effects of bisphosphonates on ectopic soft tissue mineralization caused by mutations in the ABCC6 gene","volume":"14","author":"Li","year":"2015","journal-title":"Cell Cycle"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1258","DOI":"10.1016\/j.ajpath.2017.02.009","article-title":"Pyrophosphate Supplementation Prevents Chronic and Acute Calcification in ABCC6-Deficient Mice","volume":"187","author":"Pomozi","year":"2017","journal-title":"Am. J. Pathol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1117","DOI":"10.1016\/j.jacc.2017.12.062","article-title":"Etidronate for Prevention of Ectopic Mineralization in Patients with Pseudoxanthoma Elasticum","volume":"71","author":"Kranenburg","year":"2018","journal-title":"J. Am. Coll. Cardiol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"37","DOI":"10.1016\/j.atherosclerosis.2019.10.004","article-title":"Etidronate halts systemic arterial calcification in pseudoxanthoma elasticum","volume":"292","author":"Bartstra","year":"2020","journal-title":"Atherosclerosis"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"3124","DOI":"10.1016\/j.celrep.2019.05.038","article-title":"Poly(ADP-Ribose) Links the DNA Damage Response and Biomineralization","volume":"27","author":"Muller","year":"2019","journal-title":"Cell Rep."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"2140","DOI":"10.1016\/j.jid.2022.01.022","article-title":"Inhibition of the DNA Damage Response Attenuates Ectopic Calcification in Pseudoxanthoma Elasticum","volume":"142","author":"Huang","year":"2022","journal-title":"J. Investig. Dermatol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1629","DOI":"10.1016\/j.jid.2021.10.019","article-title":"Minocycline attenuates excessive DNA damage response and reduces ectopic calcification in pseudoxanthoma elasticum","volume":"142","author":"Nollet","year":"2021","journal-title":"J. Investig. Dermatol."},{"key":"ref_23","doi-asserted-by":"crossref","unstructured":"Bouderlique, E., Nollet, L., Letavernier, E., and Vanakker, O.M. (2022). Minocycline Counteracts Ectopic Calcification in a Murine Model of Pseudoxanthoma Elasticum: A Proof-of-Concept Study. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms23031838"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"8299","DOI":"10.1128\/MCB.25.18.8299-8310.2005","article-title":"Targeted ablation of the abcc6 gene results in ectopic mineralization of connective tissues","volume":"25","author":"Klement","year":"2005","journal-title":"Mol. Cell. Biol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1227","DOI":"10.1136\/bmj.292.6530.1227","article-title":"Osteomalacia in Paget\u2019s disease treated with short term, high dose sodium etidronate","volume":"292","author":"Gibbs","year":"1986","journal-title":"Br. Med. J. (Clin. Res. Ed.)"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"19852","DOI":"10.1038\/s41598-022-23892-5","article-title":"Anticalcification effects of DS-1211 in pseudoxanthoma elasticum mouse models and the role of tissue-nonspecific alkaline phosphatase in ABCC6-deficient ectopic calcification","volume":"12","author":"Soma","year":"2022","journal-title":"Sci. Rep."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"798","DOI":"10.21037\/atm.2019.12.73","article-title":"Plasma inorganic pyrophosphate and alkaline phosphatase in patients with pseudoxanthoma elasticum","volume":"7","author":"Carrillo","year":"2019","journal-title":"Ann. Transl. Med."},{"key":"ref_28","doi-asserted-by":"crossref","unstructured":"Leftheriotis, G., Navasiolava, N., Clotaire, L., Duranton, C., Le Saux, O., Bendahhou, S., Laurain, A., Rubera, I., and Martin, L. (2022). Relationships between Plasma Pyrophosphate, Vascular Calcification and Clinical Severity in Patients Affected by Pseudoxanthoma Elasticum. J. Clin. Med., 11.","DOI":"10.3390\/jcm11092588"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/24\/20\/15041\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T21:04:10Z","timestamp":1760130250000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/24\/20\/15041"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,10,10]]},"references-count":28,"journal-issue":{"issue":"20","published-online":{"date-parts":[[2023,10]]}},"alternative-id":["ijms242015041"],"URL":"https:\/\/doi.org\/10.3390\/ijms242015041","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,10,10]]}}}