Enzyme Replacement Therapy Prevents Dental Defects in a Model of Hypophosphatasia
Enzyme Replacement Therapy Prevents Dental Defects in a Model of Hypophosphatasia
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DOI：
10.1177/0022034510393517
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发表时间：
2011-04-01
影响因子：
7.6
通讯作者：
Millan, J. L.
中科院分区：
文献类型：
--
作者：
McKee, M. D.;Nakano, Y.;Millan, J. L.
组织非特异性碱性磷酸酶(TNALP)基因发生功能缺失突变，导致细胞外焦磷蓄积，抑制骨骼和牙齿矿化。TNALP缺失的小鼠(Akp2(-/-))表现为人类婴儿低磷症；它们在1周大时出现软骨病，并在断奶前死亡，有严重的骨骼和牙齿矿化不足以及呼吸暂停和维生素B(6)反应性癫痫发作。牙本质矿化的延迟和缺陷，以及脱细胞牙骨质的缺乏是其特征。我们报告了在Akp2(-/-)小鼠中预防这些牙齿异常的方法，这些小鼠从出生起就接受每天注射矿物质靶向的人TNALP(Salp-FCD(10))治疗。根据显微计算机断层扫描和组织学的评估，SALP-FCD(10)可防止牙槽骨、牙本质和牙骨质的矿化减少。骨桥蛋白--无细胞牙骨质的标志--被免疫定位于牙根表面，证实无细胞牙骨质在Akp2(-/-)小鼠中通常缺失或减少，正常形成。我们的发现提供了关于脱细胞牙骨质是如何在牙齿表面形成，从而影响牙周韧带附着以保持牙齿在其骨性牙槽窝中的洞察力。此外，他们提供的证据表明，这种酶替代疗法，在出生后生命早期应用-大多数牙根发育发生，包括无细胞牙骨质形成-可以防止HPP患者出现的加速牙齿脱落。
Hypophosphatasia (HPP) occurs from loss-of-function mutation in the tissue-non-specific alkaline phosphatase (TNALP) gene, resulting in extracellular pyrophosphate accumulation that inhibits skeletal and dental mineralization. TNALP-null mice (Akp2(-/-)) phenocopy human infantile hypophosphatasia; they develop rickets at 1 week of age, and die before being weaned, having severe skeletal and dental hypomineralization and episodes of apnea and vitamin B(6)-responsive seizures. Delay and defects in dentin mineralization, together with a deficiency in acellular cementum, are characteristic. We report the prevention of these dental abnormalities in Akp2(-/-) mice receiving treatment from birth with daily injections of a mineral-targeting, human TNALP (sALP-FcD(10)). sALP-FcD(10) prevented hypomineralization of alveolar bone, dentin, and cementum as assessed by micro-computed tomography and histology. Osteopontin - a marker of acellular cementum - was immunolocalized along root surfaces, confirming that acellular cementum, typically missing or reduced in Akp2(-/-) mice, formed normally. Our findings provide insight concerning how acellular cementum is formed on tooth surfaces to effect periodontal ligament attachment to retain teeth in their osseous alveolar sockets. Furthermore, they provide evidence that this enzyme-replacement therapy, applied early in post-natal life - where the majority of tooth root development occurs, including acellular cementum formation - could prevent the accelerated tooth loss seen in individuals with HPP.