Inozyme Pharma, 321 Summer St, Suite 400, Boston, MA 02201, United States of America.
Inozyme Pharma, 321 Summer St, Suite 400, Boston, MA 02201, United States of America.
Bone. 2023 Jun;171:116750. doi: 10.1016/j.bone.2023.116750. Epub 2023 Mar 30.
Inorganic pyrophosphate (PP) is highly regulated as it plays a critical role in the regulation of physiological mineralization. Dysregulation of plasma PP is associated with skeletal hypomineralization and pathogenic mineralization in soft connective tissue, arteries, and heart valves. There is no standard approach to measuring PP, making it difficult to establish PP as a biomarker of mineralization disorders. This study aims to determine the impact of time of day, meals, or exercise on plasma PP homeostasis using a highly sensitive PPi assay.
In this single-center trial, a clinical laboratory improvement amendment (CLIA) validated modified sulfurylase-based adenosine 5-triphosphate (ATP) assay was used to measure PP levels throughout the day in 10 healthy adults under 3 conditions; normal diet (non-fasting), fasting, and normal diet with exercise. Serum ectonucleotide pyrophosphatase/phosphodiesterase 1 activity (ENPP1; an enzyme that produces PP) was also measured to determine whether these conditions influence PP levels through ENPP1 activity.
There is a circadian increase in mean PP levels under fasting and non-fasting conditions between 8 am and 6 pm, followed by a rapid return to baseline overnight. A circadian increase in ENPP1 activity was also measured under fasting but was lost under non-fasting conditions. Meals increased the individual variability of PP levels when compared to the same individual fasting. PP levels and ENPP1 activity exhibited a short-term increase after intense exercise. We found PP ranges from 1465 nM to 2969 nM (mean 2164 nM) after fasting overnight. Within this range, there was lower intra-subject variability in PP, suggesting that each individual has a uniquely regulated normal PP range.
Plasma levels of PP can be reliably measured after an overnight fast and show promise as a biomarker of mineralization disorders.
无机焦磷酸（PP）的调节作用十分关键，因为它在生理矿化的调节中起着重要作用。血浆 PP 的失调与骨骼矿化不足以及软组织、动脉和心脏瓣膜的病理性矿化有关。目前尚无测量 PP 的标准方法，因此难以将 PP 确立为矿化障碍的生物标志物。本研究旨在使用高度敏感的 PPi 测定法，确定昼夜节律、进餐或运动对血浆 PP 动态平衡的影响。
在这项单中心试验中，采用经过临床实验室改进修正案（CLIA）验证的改良的基于硫苷酶的三磷酸腺苷（ATP）测定法，在 3 种条件下，即正常饮食（不禁食）、禁食和正常饮食加运动，对 10 名健康成年人进行了全天的 PP 水平测量。还测量了血清核苷酸磷酸二酯酶 1 活性（ENPP1；一种产生 PP 的酶），以确定这些条件是否通过 ENPP1 活性影响 PP 水平。
在禁食和不禁食条件下，从早上 8 点到下午 6 点，PP 水平呈昼夜节律性升高，之后夜间迅速恢复到基线水平。在禁食条件下也测量到 ENPP1 活性的昼夜节律性升高，但在不禁食条件下消失。与禁食相比，进餐增加了个体的 PP 水平的个体差异。剧烈运动后，PP 水平和 ENPP1 活性会短暂升高。我们发现禁食过夜后 PP 范围为 1465 nM 至 2969 nM（平均 2164 nM）。在此范围内，PP 的个体内变异性较低，表明每个人都有独特调节的正常 PP 范围。
禁食一夜后可以可靠地测量血浆 PP 水平，有望成为矿化障碍的生物标志物。
