Asfotase-α improves bone growth, mineralization and strength in mouse models of neurofibromatosis type-1.
Asfotase-α improves bone growth, mineralization and strength in mouse models of neurofibromatosis type-1.
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骨骼的矿化取决于焦磷酸盐（PPi）（羟基磷灰石形成的抑制剂）和碱性磷酸酶（ALP）分解PPi产生的磷酸盐之间的平衡。我们在这里报告，消融NF 1，编码RAS/GTP酶激活蛋白neurofibromin，在骨形成细胞导致超生理PPi积累，引起的慢性ERK依赖性增加基因促进PPi合成和细胞外运输，即Enpp 1和Ank。它还阻止BMP 2诱导的骨祖细胞分化，从而阻止ALP和PPi的表达，进一步促进PPi积累。在骨软骨祖细胞或成骨细胞中缺乏Nf 1的小鼠的身材矮小、骨矿化和强度受损可以通过旨在降低PPi浓度的酶疗法来纠正。这些结果确立了神经纤维蛋白作为骨矿化的重要调节剂，表明PPi稳态的改变有助于与1型神经纤维瘤病（NF 1）相关的骨骼发育不良，并且某些NF 1骨骼疾病可能是可预防的。
Mineralization of the skeleton depends on the balance between levels of pyrophosphate (PPi), an inhibitor of hydroxyapatite formation, and phosphate generated from PPi breakdown by alkaline phosphatase (ALP). We report here that ablation of Nf1, encoding the RAS/GTPase–activating protein neurofibromin, in bone–forming cells leads to supraphysiologic PPi accumulation, caused by a chronic ERK–dependent increase in genes promoting PPi synthesis and extracellular transport, namely Enpp1 and Ank. It also prevents BMP2–induced osteoprogenitor differentiation and, consequently, expression of ALP and PPi breakdown, further contributing to PPi accumulation. The short stature, impaired bone mineralization and strength in mice lacking Nf1 in osteochondroprogenitors or osteoblasts could be corrected by enzyme therapy aimed at reducing PPi concentration. These results establish neurofibromin as an essential regulator of bone mineralization, suggest that altered PPi homeostasis contributes to the skeletal dysplasiae associated with neurofibromatosis type-1 (NF1), and that some of the NF1 skeletal conditions might be preventable pharmacologically.
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影响因子：
2.5
作者：
Lee DY;Cho TJ;Lee HR;Lee K;Moon HJ;Park MS;Yoo WJ;Chung CY;Choi IH
通讯作者：
Choi IH
影响因子：
4.1
作者：
MacRae, Vicky E.;Davey, Megan G.;Farquharson, Colin
通讯作者：
Farquharson, Colin
影响因子：
6.2
作者：
Johnson, K;Goding, J;Terkeltaub, R
通讯作者：
Terkeltaub, R
影响因子：
7
作者：
Alves, Rodrigo D. A. M.;Eijken, Marco;van Leeuwen, Johannes P. T. M.
通讯作者：
van Leeuwen, Johannes P. T. M.
DOI：
10.1097/01.bpb.0000194439.75378.ac
发表时间：
2006-05-01
影响因子：
1.1
作者：
Anticevic, Darko;Jelic, Mislav;Vukicevic, Slobodan
通讯作者：
Vukicevic, Slobodan