Inhibition of the DNA Damage Response Attenuates Ectopic Calcification in Pseudoxanthoma Elasticum.
Inhibition of the DNA Damage Response Attenuates Ectopic Calcification in Pseudoxanthoma Elasticum.
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DOI：
10.1016/j.jid.2022.01.022
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发表时间：
2022-08
影响因子：
6.5
通讯作者：
Li, Qiaoli
中科院分区：
文献类型：
--
作者：
Huang, Jianhe;Ralph, Douglas;Boraldi, Federica;Quaglino, Daniela;Uitto, Jouni;Li, Qiaoli
弹性假性黄瘤（PXE）是一种具有多器官临床表现的遗传性异位钙化疾病。默认基因ABCC6编码外排转运蛋白ABCC6，它是调节无机焦磷酸盐（PPi）稳态的新参与者，PPi是一种有效的内源性抗钙化因子。先前的研究表明，全身性PPi缺乏是PXE异位钙化的主要原因，但不是唯一原因。在这项研究中，我们证明了DNA损伤反应（DDR）和聚（adp -核糖）（PAR）途径在PXE的异位钙化部位局部参与。与年龄匹配的Abcc6 - / - PARP1 +/+幼崽相比，基因抑制PARP1（主要的par产生酶）显示，Abcc6 - / - PARP1 - / -小鼠的口部皮肤钙化减少54%。随后，口服二甲胺四环素（一种DDR/PAR信号抑制剂）导致Abcc6 - / -小鼠口部皮肤钙化减少86%。二甲胺四环素治疗也减弱了PXE患者的DDR/PAR信号并减少了真皮成纤维细胞的钙化。DDR/PAR抑制的抗钙化作用不伴有血浆PPi浓度的改变。这些结果表明，钙化易发组织中的局部DDR/PAR信号参与了PXE的发病机制，抑制其可能为PXE的异位钙化提供一种有希望的治疗策略，PXE是目前难治性疾病。
Pseudoxanthoma elasticum (PXE) is a heritable ectopic calcification disorder with multi-organ clinical manifestations. The gene at default, ABCC6, encodes an efflux transporter, ABCC6, which is a new player regulating the homeostasis of inorganic pyrophosphate (PPi), a potent endogenous anti-calcification factor. Previous studies suggested that systemic PPi deficiency is the major, but not the exclusive, cause of ectopic calcification in PXE. In this study, we demonstrate that the DNA damage response (DDR) and poly(ADP-ribose) (PAR) pathways are involved locally in PXE at sites of ectopic calcification. Genetic inhibition of PARP1, the predominant PAR-producing enzyme, showed a 54% reduction of calcification in the muzzle skin in Abcc6−/−Parp1−/− mice, as compared to age-matched Abcc6−/−Parp1+/+ littermates. Subsequently, oral administration of minocycline, an inhibitor of DDR/PAR signaling, resulted in an 86% reduction of calcification in the muzzle skin of Abcc6−/− mice. Minocycline treatment also attenuated the DDR/PAR signaling and reduced calcification of dermal fibroblasts derived from PXE patients. The anti-calcification effect of DDR/PAR inhibition was not accompanied by alterations in plasma PPi concentrations. These results suggest that local DDR/PAR signaling in calcification-prone tissues contributes to PXE pathogenesis, and its inhibition might provide a promising treatment strategy for ectopic calcification in PXE, a currently intractable disease.
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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：
4.6
作者：
Boraldi, Federica;Annovi, Giulia;Quaglino, Daniela
通讯作者：
Quaglino, Daniela
影响因子：
6.5
作者：
Boraldi, Federica;Bartolomeo, Angelica;Quaglino, Daniela
通讯作者：
Quaglino, Daniela
影响因子：
3.9
作者：
Luo H;Li Q;Cao Y;Uitto J
通讯作者：
Uitto J