1] Vanderbilt Center for Bone Biology, Vanderbilt University Medical Center, Nashville, Tennessee, USA. [2] Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
1] Vanderbilt Center for Bone Biology, Vanderbilt University Medical Center, Nashville, Tennessee, USA. [2] Department of Biomedical Engineering, Vanderbilt University, Nashville, Tennessee, USA. [3] Department of Orthopaedic Surgery &Rehabilitation, Vanderbilt University Medical Center, Nashville, Tennessee, USA. [4] Department of Veterans Affairs, Tennessee Valley Healthcare System, Nashville, Tennessee, USA.
Nat Med. 2014 Aug;20(8):904-10. doi: 10.1038/nm.3583. Epub 2014 Jul 6.
Individuals with neurofibromatosis type-1 (NF1) can manifest focal skeletal dysplasias that remain extremely difficult to treat. NF1 is caused by mutations in the NF1 gene, which encodes the RAS GTPase-activating protein neurofibromin. We report here that ablation of Nf1 in bone-forming cells leads to supraphysiologic accumulation of pyrophosphate (PPi), a strong inhibitor of hydroxyapatite formation, and that a chronic extracellular signal-regulated kinase (ERK)-dependent increase in expression of genes promoting PPi synthesis and extracellular transport, namely Enpp1 and Ank, causes this phenotype. Nf1 ablation also prevents bone morphogenic protein-2-induced osteoprogenitor differentiation and, consequently, expression of alkaline phosphatase and PPi breakdown, further contributing to PPi accumulation. The short stature and impaired bone mineralization and strength in mice lacking Nf1 in osteochondroprogenitors or osteoblasts can be corrected by asfotase-α enzyme therapy aimed at reducing PPi concentration. These results establish neurofibromin as an essential regulator of bone mineralization. They also suggest that altered PPi homeostasis contributes to the skeletal dysplasias associated with NF1 and that some of the NF1 skeletal conditions could be prevented pharmacologically.
患有神经纤维瘤病 1 型（NF1）的个体可能表现出局灶性骨骼发育不良，这些疾病仍然极难治疗。NF1 是由 NF1 基因的突变引起的，该基因编码 Ras GTP 酶激活蛋白神经纤维瘤。我们在这里报告，成骨细胞中 Nf1 的缺失导致焦磷酸盐（PPi）的超生理积累，PPi 是羟基磷灰石形成的强抑制剂，慢性细胞外信号调节激酶（ERK）依赖性增加促进 PPi 合成和细胞外转运的基因表达，即 Enpp1 和 Ank，导致这种表型。Nf1 缺失还可阻止骨形态发生蛋白-2 诱导的成骨前体细胞分化，从而导致碱性磷酸酶和 PPi 分解的表达减少，进一步导致 PPi 积累。缺乏成骨软骨细胞或成骨细胞中 Nf1 的小鼠的身材矮小以及骨矿物质化和强度受损，可以通过针对降低 PPi 浓度的 asfotase-α 酶疗法来纠正。这些结果确立了神经纤维瘤作为骨矿化的必需调节剂。它们还表明，改变的 PPi 动态平衡导致与 NF1 相关的骨骼发育不良，并且一些 NF1 骨骼状况可以通过药理学预防。
