| First Author | Soma K | Year | 2022 |
| Journal | Sci Rep | Volume | 12 |
| Issue | 1 | Pages | 19852 |
| PubMed ID | 36400944 | Mgi Jnum | J:331631 |
| Mgi Id | MGI:7387722 | Doi | 10.1038/s41598-022-23892-5 |
| Citation | Soma K, et al. (2022) Anticalcification effects of DS-1211 in pseudoxanthoma elasticum mouse models and the role of tissue-nonspecific alkaline phosphatase in ABCC6-deficient ectopic calcification. Sci Rep 12(1):19852 |
| abstractText | 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 ABCC6(-/-) mice after DS-1211 administration for 13-14 weeks. 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 ABCC6(-/-) mice with genetically reduced TNAP activity, ABCC6(-/-)/TNAP(+/+) and ABCC6(-/-)/TNAP(+/-). In KK/HlJ and ABCC6(-/-) 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 ABCC6(-/-) mice. Mice with ABCC6(-/-)/TNAP(+/-) phenotype had significantly less calcification and higher plasma PPi and PLP than ABCC6(-/-)/TNAP(+/+) 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. |
