Ablation of Enpp6 Results in Transient Bone Hypomineralization.
Ablation of Enpp6 Results in Transient Bone Hypomineralization.
复制标题
Enpp6的消融会导致一过性的骨矿化减少。
DOI：
10.1002/jbm4.10439
复制
发表时间：
2021-03
期刊：
影响因子：
3.8
通讯作者：
Farquharson C
中科院分区：
文献类型：
--
作者：
Dillon S;Suchacki K;Hsu SN;Stephen LA;Wang R;Cawthorn WP;Stewart AJ;Nudelman F;Morton NM;Farquharson C
生物矿化是骨骼发育的一个基本过程。磷酸酶孤儿磷酸酶1(PHOSPHO1)可能存在于细胞外基质小泡中，是生物矿化的重要调节因子。然而，产生泡内PHOSPHO1底物的生化途径目前尚不清楚。我们推测，胞外核苷酸焦磷酸/磷酸二酯酶6(ENPP6)是磷酸1底物的上游来源。为了测试这一点，我们鉴定了靶向缺失Enpp6(Enpp6−/−)纯合子小鼠的骨骼表型。小梁室的微型计算机断层扫描显示Enpp6−/−胫骨(p <； 0.05)一过性低矿化，12 周龄时恢复正常。全骨皮质分析还显示，与WT组相比，4周龄而不是12周龄的Enpp6−/−小鼠(p <； 0.05)近端骨骼矿化显著减少。背向散射扫描显示4周龄矿化灶的松质骨不能生长。静态组织形态计量学显示类骨质体积(p >； 0.0 1)和类骨质表面(p <； 0.0 5)增加，12 周后恢复，但未见成骨细胞或破骨细胞数量的变化。这项研究首次表征了Enpp6−/−小鼠的骨骼表型，揭示了与WT对照组相比，幼年动物的瞬时矿化不足。这些数据表明，ENPP6对骨矿化很重要，并且可能作为一种在基质小泡内产生底物的新方法在PHOSPHO1上游发挥作用。©2020作者。JBMR Plus由威利期刊有限责任公司出版。代表美国骨骼和矿物研究学会。
Biomineralization is a fundamental process key to the development of the skeleton. The phosphatase orphan phosphatase 1 (PHOSPHO1), which likely functions within extracellular matrix vesicles, has emerged as a critical regulator of biomineralization. However, the biochemical pathways that generate intravesicular PHOSPHO1 substrates are currently unknown. We hypothesized that the enzyme ectonucleotide pyrophosphatase/phosphodiesterase 6 (ENPP6) is an upstream source of the PHOSPHO1 substrate. To test this, we characterized skeletal phenotypes of mice homozygous for a targeted deletion of Enpp6 (Enpp6 −/−). Micro‐computed tomography of the trabecular compartment revealed transient hypomineralization in Enpp6 −/− tibias (p < 0.05) that normalized by 12 weeks of age. Whole‐bone cortical analysis also revealed significantly hypomineralized proximal bone in 4‐ but not 12‐week‐old Enpp6 −/− mice (p < 0.05) compared with WT animals. Back‐scattered SEM revealed a failure in 4‐week‐old trabecular bone of mineralization foci to propagate. Static histomorphometry revealed increased osteoid volume (p > 0.01) and osteoid surface (p < 0.05), which recovered by 12 weeks but was not accompanied by changes in osteoblast or osteoclast number. This study is the first to characterize the skeletal phenotype of Enpp6 −/− mice, revealing transient hypomineralization in young animals compared with WT controls. These data suggest that ENPP6 is important for bone mineralization and may function upstream of PHOSPHO1 as a novel means of generating its substrates inside matrix vesicles. © 2020 The Authors. JBMR Plus published by Wiley Periodicals LLC. on behalf of American Society for Bone and Mineral Research.