Anticalcification effects of DS-1211 in pseudoxanthoma elasticum mouse models and the role of tissue-nonspecific alkaline phosphatase in ABCC6-deficient ectopic calcification.
Anticalcification effects of DS-1211 in pseudoxanthoma elasticum mouse models and the role of tissue-nonspecific alkaline phosphatase in ABCC6-deficient ectopic calcification.
复制标题
DOI：
10.1038/s41598-022-23892-5
复制
发表时间：
2022-11-18
影响因子：
4.6
通讯作者：
中科院分区：
文献类型：
--
作者：
弹性假黄瘤是一种多系统、遗传性的异位矿化疾病，目前尚无有效的治疗方法。抑制组织非特异性碱性磷酸酶(TNAP)可能通过增加内源性焦磷酸(PPI)来防止异位软组织钙化。本研究评价了DS-1211在PXE小鼠模型中的抗钙化作用，DS-1211是一种口服的、有效的、高选择性的小分子TNAP抑制剂。KK/HlJ和ABCC6-/-小鼠在DS-1211给药13-14周后测定触须中钙含量。评价DS-1211的药代动力学和药效学效应，包括血浆碱性磷酸酶(ALP)活性、PPI和磷酸吡哆醛(PLP)生物标志物的变化。进一步评估了DS-1211通过抑制TNAP在ABCC6-/-小鼠中的抗钙化作用，这些小鼠具有遗传降低的TNAP活性，ABCC6-/-/TNAP+/+和ABCC6-/-/TNAP+/-。在KK/HlJ和ABCC6-/-小鼠模型中，DS-1211以剂量依赖的方式抑制血浆ALP活性，并与赋形剂治疗的小鼠相比，阻止异位钙化的进展。DS-1211可剂量依赖性增加ABCC6-/-小鼠血浆PPI和PLP水平。ABCC6-/-/TNAP+/-表型小鼠的钙化程度显著低于ABCC6-/-/TNAP+/+小鼠，而血浆PPI和PLP显著高于ABCC6-/-/TNAP+/+小鼠。TNAP在钙化失调的病理机制中发挥着积极的作用，在TNAP活性较低的小鼠的异位钙化减少中得到了证明。DS-1211可能是一种治疗PXE的潜在药物。
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.
登录
查看更多内容
DOI：
10.1073/pnas.1319582110
发表时间：
2013-12-10
影响因子：
11.1
作者：
Jansen, Robert S.;Kucukosmanoglu, Asli;van de Wetering, Koen
通讯作者：
van de Wetering, Koen
影响因子：
11.1
作者：
Dedinszki D;Szeri F;Kozák E;Pomozi V;Tőkési N;Mezei TR;Merczel K;Letavernier E;Tang E;Le Saux O;Arányi T;van de Wetering K;Váradi A
通讯作者：
Váradi A
影响因子：
4.7
作者：
Li, Qiaoli;Uitto, Jouni
通讯作者：
Uitto, Jouni
DOI：
10.1016/j.jid.2016.12.014
发表时间：
2017-04
期刊：
The Journal of investigative dermatology
影响因子：
--
作者：
Uitto J;Li Q;van de Wetering K;Váradi A;Terry SF
通讯作者：
Terry SF
影响因子：
4.2
作者：
Millán JL;Whyte MP
通讯作者：
Whyte MP