Center for Metabolic Bone Disease and Molecular Research, Shriners Hospitals for Children - St Louis, St. Louis, MO 63110, USA; Division of Bone and Mineral Diseases, Department of Internal Medicine, Washington University School of Medicine at Barnes-Jewish Hospital, St. Louis, MO 63110, USA.
Center for Metabolic Bone Disease and Molecular Research, Shriners Hospitals for Children - St Louis, St. Louis, MO 63110, USA.
Bone. 2020 May;134:115300. doi: 10.1016/j.bone.2020.115300. Epub 2020 Feb 26.
Hypophosphatasia (HPP) is the inborn-error-of-metabolism caused by loss-of-function mutation(s) of the ALPL gene that encodes the tissue-nonspecific isoenzyme of alkaline phosphatase (TNSALP). TNSALP in healthy individuals is on cell surfaces richly in bone, liver, and kidney. Thus, TNSALP natural substrates accumulate extracellularly in HPP, including inorganic pyrophosphate (PPi), a potent inhibitor of hydroxyapatite crystal formation and growth. Superabundance of extracellular PPi (ePPi) in HPP impairs mineralization of bones and teeth, often leading to rickets during childhood and osteomalacia in adult life and to tooth loss at any age. HPP's remarkably broad-ranging severity is largely explained by nearly four hundred typically missense mutations throughout the ALPL gene that are transmitted as an autosomal dominant or autosomal recessive trait. In the clinical laboratory, the biochemical hallmark of HPP is low serum ALP activity (hypophosphatasemia). However, our experience indicates that hyperphosphatemia from increased renal reclamation of filtered inorganic phosphate (Pi) is also common. Herein, from our prospective single-center study, we document throughout the clinical spectrum of non-lethal pediatric HPP that hyperphosphatemia reflects increased renal tubular threshold maximum for phosphorus adjusted for the glomerular filtration rate (TmP/GFR). To explore its pathogenesis, we studied mineral metabolism and quantitated circulating levels of three phosphatonins [fibroblast growth factor 23 (FGF23), secreted frizzled-related protein 4 (sFRP4), and fibroblast growth factor 7 (FGF7)] in 41 pediatric patients with HPP, 73 with X-linked hypophosphatemia (XLH), and 15 healthy pediatric control (CTR) subjects. The HPP and XLH cohorts had normal serum total and ionized calcium and parathyroid hormone levels (Ps > 0.10) and uncompromised glomerular filtration. In XLH, serum FGF23 was characteristically elevated (P < 0.0001) and despite hypophosphatemia sFRP4 was normal (P > 0.4) while FGF7 was low (P < 0.0001). In HPP, despite hyperphosphatemia serum FGF23 and sFRP4 were normal (Ps > 0.8) while FGF7 was low (P < 0.0001). Subsequently, in rats, we confirmed that FGF7 is phosphaturic. Thus, hyperphosphatemia in non-lethal pediatric HPP is associated with phosphatonin insufficiency together with, as we discuss, ePPi excess and diminished renal TNSALP activity.
低磷酸酯酶症（HPP）是一种先天性代谢缺陷疾病，由碱性磷酸酶（ALPL）基因的功能丧失突变引起。在健康个体中，TNSALP 大量存在于富含骨、肝和肾的细胞表面。因此，HPP 中 TNSALP 的天然底物在细胞外积聚，包括无机焦磷酸盐（PPi），这是一种抑制羟基磷灰石晶体形成和生长的有效抑制剂。HPP 中细胞外过多的 PPi（ePPi）会损害骨骼和牙齿的矿化，这通常会导致儿童时期的佝偻病和成年期的骨软化症，并导致任何年龄的牙齿脱落。HPP 广泛的严重程度在很大程度上可以用 ALPL 基因中近四百个典型的错义突变来解释，这些突变作为常染色体显性或常染色体隐性遗传特征传递。在临床实验室中，HPP 的生化特征是血清碱性磷酸酶活性降低（低磷酸血症）。然而，我们的经验表明，由于肾脏对过滤的无机磷酸盐（Pi）的再吸收增加而导致的高磷酸盐血症也很常见。在此，我们从前瞻性单中心研究中记录了非致死性儿科 HPP 的整个临床谱，高磷酸盐血症反映了调整肾小球滤过率（GFR）后的肾小管磷最大重吸收阈值增加（TmP/GFR）。为了探讨其发病机制，我们研究了矿物质代谢，并在 41 名 HPP 儿科患者、73 名 X 连锁低磷血症（XLH）患者和 15 名健康儿科对照（CTR）受试者中定量检测了三种磷调素[成纤维细胞生长因子 23（FGF23）、分泌卷曲相关蛋白 4（sFRP4）和成纤维细胞生长因子 7（FGF7）]的循环水平。HPP 和 XLH 队列的血清总钙和离子钙以及甲状旁腺激素水平正常（Ps>0.10），肾小球滤过功能不受影响。在 XLH 中，血清 FGF23 特征性升高（P<0.0001），尽管存在低磷血症，但 sFRP4 正常（P>0.4），而 FGF7 水平降低（P<0.0001）。在 HPP 中，尽管存在高磷酸盐血症，但血清 FGF23 和 sFRP4 正常（Ps>0.8），而 FGF7 水平降低（P<0.0001）。随后，在大鼠中，我们证实了 FGF7 具有排磷作用。因此，非致死性儿科 HPP 中的高磷酸盐血症与磷调素不足有关，此外，正如我们所讨论的，还与 ePPi 过多和肾脏 TNSALP 活性降低有关。
