Genetic and pharmacologic modulation of cementogenesis via pyrophosphate regulators
Genetic and pharmacologic modulation of cementogenesis via pyrophosphate regulators
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DOI：
10.1016/j.bone.2020.115329
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发表时间：
2020-07-01
期刊：
影响因子：
4.1
通讯作者：
Somerman, M. J.
中科院分区：
文献类型：
--
作者：
Chu, E. Y.;Vo, T. D.;Somerman, M. J.
焦磷酸盐（PPi）是一种有效的生理重要的矿化调节剂，全身和局部浓度由几种关键调节剂决定，包括：组织非特异性碱性磷酸酶（ALPL基因; TNAP蛋白）、进行性关节强直蛋白（ANKH; ANK）和外核苷酸焦磷酸酶/磷酸二酯酶1（ENPP 1; ENPP 1）。迄今为止的结果表明PPi在牙骨质形成中的重要作用，我们通过采用PPi代谢被破坏的基因编辑的小鼠模型和PPi缺陷小鼠模型中的PPi调节蛋白来解决知识上的几个空白。我们证明，无细胞牙骨质生长与PPi水平成反比，Alpl KO小鼠牙骨质减少（PPi水平升高），Ank KO小鼠牙骨质过量（PPi水平降低）。此外，Alpl和Ank的同时消融导致dKO小鼠中功能性牙骨质的重建。通过Ank和Enpp1的双重缺失进一步减少PPi不会进一步增加牙骨质形成，PDL空间部分通过破骨细胞的骨建模/重塑来维持。我们的研究结果提供了深入了解牙骨质形成和扩大我们的知识PPi如何调节牙骨质。我们还首次证明了通过ENPP1-Fc融合蛋白对PPi进行药理学操作可以调节牙骨质生长，支持针对PPi代谢的治疗干预。
Pyrophosphate (PPi) serves as a potent and physiologically important regulator of mineralization, with systemic and local concentrations determined by several key regulators, including: tissue-nonspecific alkaline phosphatase (ALPL gene; TNAP protein), the progressive ankylosis protein (ANKH; ANK), and ectonucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1; ENPP1). Results to date have indicated important roles for PPi in cementum formation, and we addressed several gaps in knowledge by employing genetically edited mouse models where PPi metabolism was disrupted and pharmacologically modulating PPi in a PPi-deficient mouse model. We demonstrate that acellular cementum growth is inversely proportional to PPi levels, with reduced cementum in Alpl KO (increased PPi levels) mice and excess cementum in Ank KO mice (decreased PPi levels). Moreover, simultaneous ablation of Alpl and Ank results in reestablishment of functional cementum in dKO mice. Additional reduction of PPi by dual deletion of Ank and Enpp1 does not further increase cementogenesis, and PDL space is maintained in part through bone modeling/remodeling by osteoclasts. Our results provide insights into cementum formation and expand our knowledge of how PPi regulates cementum. We also demonstrate for the first time that pharmacologic manipulation of PPi through an ENPP1-Fc fusion protein can regulate cementum growth, supporting therapeutic interventions targeting PPi metabolism.