A mathematical model of osteoclast acidification during bone resorption.
A mathematical model of osteoclast acidification during bone resorption.
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DOI：
10.1016/j.bone.2016.09.007
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发表时间：
2016-12
期刊：
影响因子：
4.1
通讯作者：
Grabe, Michael
中科院分区：
文献类型：
--
作者：
Marcoline, Frank V.;Ishida, Yoichi;Mindell, Joseph A.;Nayak, Smita;Grabe, Michael
破骨细胞的骨吸收是通过在骨附近形成一个封闭的细胞外室（ECC）或小窝而发生的，随后通过一个复杂的生物过程酸化。小坑的低pH值溶解骨矿物质并激活酸性蛋白酶，进一步分解骨基质。有许多离子通道，转运蛋白和可溶性蛋白参与破骨细胞介导的吸收，在过去的几年里，人们对一些关键蛋白质的身份和性质有了更多的了解，如ClC-7 Cl−/H+反向转运蛋白和HV 1质子通道。在这里，我们提出了一个详细的破骨细胞酸化的数学模型，包括许多关键的调节蛋白的影响。负责酸化的主要酶是液泡H+-ATP酶（V-ATP酶），它将质子从细胞质泵入纹孔。与小溶酶体的酸化不同，这个小坑非常大，以至于质子从细胞质中耗尽。因此，质子缓冲和碳酸酐酶II（CAII）在细胞质中的生产是适当的酸化潜在的重要。我们采用了一个常微分方程（ODE）为基础的模型，占在细胞质中的离子种类的变化和再吸收坑。此外，我们的模型跟踪细胞质和细胞周围的细胞外溶液之间的离子流。只要有可能，基于电生理学测量校准单个通道和转运蛋白的性质，并基于可用数据估计细胞的物理性质，例如缓冲能力、表面积和体积。我们的模型再现了许多关于酸化过程中关键蛋白质作用的实验发现，它使我们能够估计，除其他外，活跃泵的数量，质子移动，以及与疾病有关的特定突变的影响。
Bone resorption by osteoclasts occurs through the creation of a sealed extracellular compartment (ECC), or pit, adjacent to the bone that is subsequently acidified through a complex biological process. The low pH of the pit dissolves the bone mineral and activates acid proteases that further break down the bone matrix. There are many ion channels, transporters, and soluble proteins involved in osteoclast mediated resorption, and in the past few years, there has been an increased understanding of the identity and properties of some key proteins such as the ClC-7 Cl−/H+ antiporter and the HV1 proton channel. Here we present a detailed mathematical model of osteoclast acidification that includes the influence of many of the key regulatory proteins. The primary enzyme responsible for acidification is the vacuolar H+-ATPase (V-ATPase), which pumps protons from the cytoplasm into the pit. Unlike the acidification of small lysosomes, the pit is so large that protons become depleted from the cytoplasm. Hence, proton buffering and production in the cytoplasm by carbonic anhydrase II (CAII) is potentially important for proper acidification. We employ an ordinary differential equations (ODE)-based model that accounts for the changes in ionic species in the cytoplasm and the resorptive pit. Additionally, our model tracks ionic flow between the cytoplasm and the extracellular solution surrounding the cell. Whenever possible, the properties of individual channels and transporters are calibrated based on electrophysiological measurements, and physical properties of the cell, such as buffering capacity, surface areas, and volumes, are estimated based on available data. Our model reproduces many of the experimental findings regarding the role of key proteins in the acidification process, and it allows us to estimate, among other things, number of active pumps, protons moved, and the influence of particular mutations implicated in disease.
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