Laboratory of Oral Connective Tissue Biology, National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), National Institutes of Health (NIH), Bethesda, MD, USA.
Craniofacial and Skeletal Diseases Branch, National Institute of Dental and Craniofacial Research (NIDCR), National Institutes of Health (NIH), Bethesda, MD, USA.
J Dent Res. 2021 Jun;100(6):639-647. doi: 10.1177/0022034520981854. Epub 2020 Dec 24.
Biomineralization is regulated by inorganic pyrophosphate (PP), 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 PP, 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 PP) resulted in increased cementum formation, suggesting PP metabolism may be a target for periodontal regenerative therapies. To compare the effects of genetic ablation of , and both factors concurrently on cementum and AB regeneration, mandibular fenestration defects were created in knockout ( KO), mutant (), and double KO (dKO) mice. Genetic ablation of , or both factors increased cementum regeneration compared to controls at postoperative days (PODs) 15 and 30 ( KO: 8-fold, 3-fold; : 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), osteopontin (/OPN), and bone sialoprotein (/BSP). Furthermore, dKO mice featured increased cementum thickness compared to single KOs at POD15 and 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 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 PP 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 PP conditions highlight the need to consider tissue-specific responses in strategies targeting regeneration of the entire periodontal complex.
生物矿化受无机焦磷酸（PP）调节，PP 是抑制羟磷灰石晶体生长的有效生理抑制剂。渐进性粘连蛋白（ANK）和核苷酸外切焦磷酸酶/磷酸二酯酶 1（ENPP1）的作用是增加局部细胞外 PP 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），两者对于牙齿附着都是必不可少的。先前的研究表明，ANK 或 ENPP1 功能丧失（减少 PP）会导致牙骨质形成增加，这表明 PP 代谢可能是牙周再生治疗的一个靶点。为了比较遗传消融 和同时消融这两种因素对牙骨质和 AB 再生的影响，在 基因敲除（KO）、 突变（）和双 KO（dKO）小鼠中创建了下颌骨开窗缺陷。与对照组相比，在术后第 15 天和 30 天（KO：8 倍，3 倍；：7 倍，3 倍；dKO：11 倍，4 倍），ANK 或两种因素的遗传消融导致牙骨质再生增加，分别与氟标记和矿化组织标志物的表达增加有关，包括牙本质基质蛋白 1（/DMP1）、骨桥蛋白（/OPN）和骨唾液蛋白（/BSP）。此外，与单 KO 相比，dKO 小鼠在 POD15 时牙骨质厚度增加，与 KO 相比在 POD30 时牙骨质厚度增加。各基因型之间 AB 体积无差异，但所有 KO 中的成骨细胞/成骨细胞标志物增加，与对照组相比，dKO 中的部分矿化骨样体体积在 POD15 时增加（3 倍），POD30 时的矿化密度降低（6%和 9%）。与对照组相比，所有 KO 中的再生 AB 中都有更多的破骨细胞。这些临床前研究表明，PP 调节可能是一种有潜力的新型牙骨质再生方法，特别是针对 ENPP1 和/或 ANK。减少 PP 条件下对牙骨质和 AB 再生的不同反应突出表明，在针对整个牙周复合体再生的策略中，需要考虑组织特异性反应。
