Tissue-nonspecific alkaline phosphatase and plasma cell membrane glycoprotein-1 are central antagonistic regulators of bone mineralization
Tissue-nonspecific alkaline phosphatase and plasma cell membrane glycoprotein-1 are central antagonistic regulators of bone mineralization
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DOI：
10.1073/pnas.142063399
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发表时间：
2002-07-09
影响因子：
11.1
通讯作者：
Millán, JL
中科院分区：
文献类型：
--
作者：
Hessle, L;Johnson, KA;Millán, JL
成骨细胞通过促进羟磷灰石晶体在膜限制的基质囊泡（MV）内部的形成和生长以及通过将晶体传播到胶原性细胞外基质上来矿化骨基质。两种成骨细胞蛋白，组织非特异性碱性磷酸酶（TNAP）和浆细胞膜糖蛋白-1（PC-1）参与了这一过程。TNAP基因的突变导致称为低磷酸酶症的先天性代谢缺陷，其特征在于骨矿化不良、自发性骨折和无机焦磷酸盐（PPi）的细胞外浓度升高。PPi抑制羟基磷灰石晶体的形成和生长。PPi是由一个同工酶家族的核苷三磷酸焦磷酸水解酶活性产生的，其中PC-1是MV中存在的唯一成员。在PC-1基因中具有自发突变的小鼠具有过度矿化异常，包括骨关节炎和脊柱后纵韧带骨化。在这里，我们展示了TNAP（Akp 2）和PC-1（Enpp 1）基因敲除小鼠中骨矿化异常的相应校正。Akp 2和Enpp 1的每个等位基因对体内矿化状态具有可测量的影响。使用培养的双敲除成骨细胞及其MV的离体实验证明PPi含量和矿物质沉积的正常化。我们的数据提供的证据表明，TNAP和PC-11是控制骨矿化所需的细胞外PPi浓度的关键调节剂。我们的研究结果表明，抑制PC-11功能可能是一个可行的治疗策略低磷酸酯酶症。相反，干扰TNAP活性可以纠正由于PPi不足而导致的病理性骨化过度。
Osteoblasts mineralize bone matrix by promoting hydroxyapatite crystal formation and growth in the interior of membrane-limited matrix vesicles (MVs) and by propagating the crystals onto the collagenous extracellular matrix. Two osteoblast proteins, tissue-nonspecific alkaline phosphatase (TNAP) and plasma cell membrane glycoprotein-1 (PC-1) are involved in this process. Mutations in the TNAP gene result in the inborn error of metabolism known as hypophosphatasia, characterized by poorly mineralized bones, spontaneous fractures, and elevated extracellular concentrations of inorganic pyrophosphate (PPi). PPi suppresses the formation and growth of hydroxyapatite crystals. PPi is produced by the nucleoside triphosphate pyrophosphohydrolase activity of a family of isozymes, with PC-1 being the only member present in MVs. Mice with spontaneous mutations in the PC-1 gene have hypermineralization abnormalities that include osteoarthritis and ossification of the posterior longitudinal ligament of the spine. Here, we show the respective correction of bone mineralization abnormalities in knockout mice null for both the TNAP (Akp2) and PC-1 (Enpp1) genes. Each allele of Akp2 and Enpp1 has a measurable influence on mineralization status in vivo. Ex vivo experiments using cultured double-knockout osteoblasts and their MVs demonstrate normalization of PPi content and mineral deposition. Our data provide evidence that TNAP and PC-11 are key regulators of the extracellular PPi concentrations required for controlled bone mineralization. Our results suggest that inhibiting PC-11 function may be a viable therapeutic strategy for hypophosphatasia. Conversely, interfering with TNAP activity may correct pathological hyperossification because of PPi insufficiency.