Ablation of Pyrophosphate Regulators Promotes Periodontal Regeneration
Ablation of Pyrophosphate Regulators Promotes Periodontal Regeneration
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DOI：
10.1177/0022034520981854
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发表时间：
2021-06-01
影响因子：
7.6
通讯作者：
Somerman, M. J.
中科院分区：
文献类型：
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作者：
Nagasaki, A.;Nagasaki, K.;Somerman, M. J.
无机焦磷酸盐（PPi）是一种有效的羟基磷灰石晶体生长生理抑制剂，可调节生物矿化。进行性强直蛋白（ANK）和外核苷酸焦磷酸酶/磷酸二酯酶1（ENPP 1）的作用是增加PPi的局部细胞外水平，抑制矿化。牙周复合体包括2种矿化组织，牙骨质和牙槽骨（AB），两者都是牙齿附着所必需的。先前的研究表明，ANK或ENPP 1功能的丧失（减少PPi）导致牙骨质形成增加，这表明PPi代谢可能是牙周再生治疗的目标。为了比较Ank、Enpp 1以及这两种因子的基因消融对牙骨质和AB再生的影响，在Ank敲除（Ank KO）、Enpp 1突变体（Enpp 1（asj/asj））和双KO（dKO）小鼠中创建下颌开窗缺损。与术后第15天和第30天（POD）的对照组相比，Ank、Enpp 1或这两种因子的基因消融增加了牙骨质再生（Ank KO：8倍，3倍; Enpp 1（asj/asj）：7倍，3倍; dKO：分别为11倍、4倍），与荧光标记和矿化组织标记物牙本质基质蛋白1表达增加相关骨桥蛋白（Spp 1/OPN）和骨唾液酸蛋白（Ibsp/BSP）。此外，与POD 15的单一科斯和POD 30的Ank KO相比，dKO小鼠的特征是牙骨质厚度增加。基因型之间的AB体积没有差异，但成骨细胞/骨细胞标记物在所有科斯中增加，部分矿化的类骨质体积在POD 15时在dKO中比对照增加（3倍），并且在POD 30时在Enpp 1（asj/asj）和d科斯中矿物质密度降低（分别为6%和9%）。与对照组相比，所有科斯的再生AB中破骨细胞数量增加。这些临床前研究表明PPi调节作为牙骨质再生的潜在和新的方法，特别是靶向ENPP 1和/或ANK。牙骨质和AB再生的差异，以减少PPi的条件下，突出需要考虑组织特异性的反应，在整个牙周复合体的再生为目标的战略。
Biomineralization is regulated by inorganic pyrophosphate (PPi), a potent physiological inhibitor of hydroxyapatite crystal growth. Progressive ankylosis protein (ANK) and ectonucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1) act to increase local extracellular levels of PPi, inhibiting mineralization. The periodontal complex includes 2 mineralized tissues, cementum and alveolar bone (AB), both essential for tooth attachment. Previous studies demonstrated that loss of function of ANK or ENPP1 (reducing PPi) resulted in increased cementum formation, suggesting PPi metabolism may be a target for periodontal regenerative therapies. To compare the effects of genetic ablation of Ank, Enpp1, and both factors concurrently on cementum and AB regeneration, mandibular fenestration defects were created in Ank knockout (Ank KO), Enpp1 mutant (Enpp1(asj/asj)), and double KO (dKO) mice. Genetic ablation of Ank, Enpp1, or both factors increased cementum regeneration compared to controls at postoperative days (PODs) 15 and 30 (Ank KO: 8-fold, 3-fold; Enpp1(asj/asj): 7-fold, 3-fold; dKO: 11-fold, 4-fold, respectively) associated with increased fluorochrome labeling and expression of mineralized tissue markers, dentin matrix protein 1 (Dmp1/DMP1), osteopontin (Spp1/OPN), and bone sialoprotein (Ibsp/BSP). Furthermore, dKO mice featured increased cementum thickness compared to single KOs at POD15 and Ank KO at POD30. No differences were noted in AB volume between genotypes, but osteoblast/osteocyte markers were increased in all KOs, partially mineralized osteoid volume was increased in dKO versus controls at POD15 (3-fold), and mineral density was decreased in Enpp1(asj/asj) and dKOs at POD30 (6% and 9%, respectively). Increased numbers of osteoclasts were present in regenerated AB of all KOs versus controls. These preclinical studies suggest PPi modulation as a potential and novel approach for cementum regeneration, particularly targeting ENPP1 and/or ANK. Differences in cementum and AB regeneration in response to reduced PPi conditions highlight the need to consider tissue-specific responses in strategies targeting regeneration of the entire periodontal complex.