Minocycline Counteracts Ectopic Calcification in a Murine Model of Pseudoxanthoma Elasticum: A Proof-of-Concept Study.
Minocycline Counteracts Ectopic Calcification in a Murine Model of Pseudoxanthoma Elasticum: A Proof-of-Concept Study.
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DOI：
10.3390/ijms23031838
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发表时间：
2022-02-06
影响因子：
5.6
通讯作者：
Vanakker OM
中科院分区：
文献类型：
--
作者：
Bouderlique E;Nollet L;Letavernier E;Vanakker OM
弹性假黄瘤 (PXE) 是一种难治性孟德尔病，其特征是皮肤、眼睛和血管异位钙化。最近，DNA 损伤反应 (DDR) 激活的增加被证明与 PXE 发病机制有关，而 DDR/PARP1 抑制剂米诺环素被发现可以减弱 PXE 细胞和斑马鱼中的异常矿化。在这项概念验证研究中，我们评估了米诺环素在 Abcc6−/− 小鼠（一种已建立的哺乳动物 PXE 模型）中的抗钙化特性。 Abcc6−/− 小鼠在 12 至 36 周龄期间接受口服米诺环素补充剂（40 毫克/公斤/天），并与未经治疗的 Abcc6−/− 和 Abcc6+/+ 兄弟姐妹进行比较。使用 X 射线显微断层扫描、口吻皮肤钙沉积的三维重建和安江钙染色来评估异位钙化。还对关键 DDR 标记 H2AX 进行了免疫组织化学分析。米诺环素治疗后，与未经治疗的 Abcc6−/− 小鼠相比，Abcc6−/− 小鼠的异位钙化显着减少（−43.4%，p < 0.0001）。 H2AX 免疫染色揭示了未经处理的 Abcc6−/− 动物中异常矿化部位的 DDR 激活。总之，我们首次在 Abcc6−/− 小鼠中验证了米诺环素的抗钙化作用。考虑到其对人体良好的安全性和作为仿制药的低成本，米诺环素可能是 PXE 患者的一种有前途的治疗化合物。
Pseudoxanthoma elasticum (PXE) is an intractable Mendelian disease characterized by ectopic calcification in skin, eyes and blood vessels. Recently, increased activation of the DNA damage response (DDR) was shown to be involved in PXE pathogenesis, while the DDR/PARP1 inhibitor minocycline was found to attenuate aberrant mineralization in PXE cells and zebrafish. In this proof-of-concept study, we evaluated the anticalcifying properties of minocycline in Abcc6−/− mice, an established mammalian PXE model. Abcc6−/− mice received oral minocycline supplementation (40 mg/kg/day) from 12 to 36 weeks of age and were compared to untreated Abcc6−/− and Abcc6+/+ siblings. Ectopic calcification was evaluated using X-ray microtomography with three-dimensional reconstruction of calcium deposits in muzzle skin and Yasue’s calcium staining. Immunohistochemistry for the key DDR marker H2AX was also performed. Following minocycline treatment, ectopic calcification in Abcc6−/− mice was significantly reduced (−43.4%, p < 0.0001) compared to untreated Abcc6−/− littermates. H2AX immunostaining revealed activation of the DDR at sites of aberrant mineralization in untreated Abcc6−/− animals. In conclusion, we validated the anticalcifying effect of minocycline in Abcc6−/− mice for the first time. Considering its favorable safety profile in humans and low cost as a generic drug, minocycline may be a promising therapeutic compound for PXE patients.
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DOI：
10.1038/jid.2008.391
发表时间：
2009-06
期刊：
The Journal of investigative dermatology
影响因子：
--
作者：
通讯作者：
--
影响因子：
24
作者：
Chen J;Budoff MJ;Reilly MP;Yang W;Rosas SE;Rahman M;Zhang X;Roy JA;Lustigova E;Nessel L;Ford V;Raj D;Porter AC;Soliman EZ;Wright JT Jr;Wolf M;He J;CRIC Investigators
通讯作者：
CRIC Investigators
影响因子：
6.5
作者：
Boraldi, Federica;Annovi, Giulia;Quaglino, Daniela
通讯作者：
Quaglino, Daniela
影响因子：
24
作者：
Lanzer P;Hannan FM;Lanzer JD;Janzen J;Raggi P;Furniss D;Schuchardt M;Thakker R;Fok PW;Saez-Rodriguez J;Millan A;Sato Y;Ferraresi R;Virmani R;St Hilaire C
通讯作者：
St Hilaire C
影响因子：
3.5
作者：
Gorgels, TGMF;Hu, XF;Bergen, AAB
通讯作者：
Bergen, AAB