ENPP1 enzyme replacement therapy improves ectopic calcification but does not rescue skeletal phenotype in a mouse model for craniometaphyseal dysplasia.

IF 3.4 Q2 ENDOCRINOLOGY & METABOLISM JBMR Plus Pub Date : 2024-08-08 eCollection Date: 2024-09-01 DOI:10.1093/jbmrpl/ziae103
Ernst J Reichenberger, Kevin O'Brien, Ayano Hatori, Thomas O Carpenter, Koen van de Wetering, Lisa Flaman, Jennifer Howe, Daniel Ortiz, Yves Sabbagh, I-Ping Chen
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Abstract

Craniometaphyseal dysplasia (CMD) is a rare genetic bone disorder, characterized by progressive thickening of craniofacial bones and flared metaphyses of long bones. Craniofacial hyperostosis leads to the obstruction of neural foramina and neurological symptoms such as facial palsy, blindness, deafness, or severe headache. Mutations in ANKH (mouse ortholog ANK), a transporter of small molecules such as citrate and ATP, are responsible for autosomal dominant CMD. Knock-in (KI) mice carrying an ANKF377del mutation (AnkKI/KI ) replicate many features of human CMD. Pyrophosphate (PPi) levels in plasma are significantly reduced in AnkKI/KI mice. PPi is a potent inhibitor of mineralization. To examine the extent to which restoration of circulating PPi levels may prevent the development of a CMD-like phenotype, we treated AnkKI/KI mice with the recombinant human ENPP1-Fc protein IMA2a. ENPP1 hydrolyzes ATP into AMP and PPi. Male and female Ank+/+ and AnkKI/KI mice (n ≥ 6/group) were subcutaneously injected with IMA2a or vehicle weekly for 12 wk, starting at the age of 1 wk. Plasma ENPP1 activity significantly increased in AnkKI/KI mice injected with IMA2a (Vehicle/IMA2a: 28.15 ± 1.65/482.7 ± 331.2 mOD/min; p <.01), which resulted in the successful restoration of plasma PPi levels (Ank+/+ /AnkKI/KI vehicle treatment/AnkKI/KI IMA2a: 0.94 ± 0.5/0.43 ± 0.2/1.29 ± 0.8 μM; p <.01). We examined the skeletal phenotype by X-Ray imaging and μCT. IMA2a treatment of AnkKI/KI mice did not significantly correct CMD features such as the abnormal shape of femurs, increased bone mass of mandibles, hyperostotic craniofacial bones, or the narrowed foramen magnum. However, μCT imaging showed ectopic calcification near basioccipital bones at the level of the foramen magnum and on joints of AnkKI/KI mice. Interestingly, IMA2a treatment significantly reduced the volume of calcified nodules at both sites. Our data demonstrate that IMA2a is sufficient to restore plasma PPi levels and reduce ectopic calcification but fails to rescue skeletal abnormalities in AnkKI/KI mice under our treatment conditions.

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ENPP1酶替代疗法可改善异位钙化,但不能挽救颅骨骨骺发育不良小鼠模型的骨骼表型。
颅骨骨骺发育不良(CMD)是一种罕见的遗传性骨骼疾病,其特征是颅面骨进行性增厚和长骨骨骺外翻。颅面骨质增生会导致神经孔阻塞和神经系统症状,如面瘫、失明、耳聋或剧烈头痛。ANKH(小鼠直向同源物 ANK)是柠檬酸盐和 ATP 等小分子的转运体,它的突变是常染色体显性 CMD 的原因。携带 ANKF377del 突变的基因敲入(KI)小鼠(AnkKI/KI)复制了人类 CMD 的许多特征。AnkKI/KI 小鼠血浆中焦磷酸(PPi)的水平显著降低。PPi 是一种有效的矿化抑制剂。为了研究恢复循环中的 PPi 水平能在多大程度上防止 CMD 类表型的形成,我们用重组人 ENPP1-Fc 蛋白 IMA2a 处理 AnkKI/KI 小鼠。ENPP1将ATP水解为AMP和PPi。雄性和雌性 Ank+/+ 和 AnkKI/KI 小鼠(n ≥ 6/组)从 1 周龄开始,每周皮下注射 IMA2a 或载体,持续 12 周。注射 IMA2a 的 AnkKI/KI 小鼠血浆 ENPP1 活性显著增加(载体/IMA2a:28.15 ± 1.65/482.7 ± 331.2 mOD/min;p Ank+/+ /AnkKI/KI 载体治疗/AnkKI/KI IMA2a:0.94 ± 0.5/0.43 ± 0.2/1.29 ± 0.8 μM; p AnkKI/KI 小鼠并未显著纠正 CMD 的特征,如股骨形状异常、下颌骨骨量增加、颅面部骨骼过度骨化或枕骨大孔狭窄。不过,μCT 成像显示,AnkKI/KI 小鼠枕骨基底附近的枕骨大孔水平和关节处有异位钙化。有趣的是,IMA2a 治疗可显著减少这两个部位钙化结节的体积。我们的数据表明,在我们的治疗条件下,IMA2a足以恢复血浆PPi水平并减少异位钙化,但却不能挽救AnkKI/KI小鼠的骨骼异常。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
JBMR Plus
JBMR Plus Medicine-Orthopedics and Sports Medicine
CiteScore
5.80
自引率
2.60%
发文量
103
审稿时长
8 weeks
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