Anabolic actions of parathyroid hormone in a hypophosphatasia mouse model,Osteoporosis International

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Anabolic actions of parathyroid hormone in a hypophosphatasia mouse model
Osteoporosis International ( IF 4.2 ) Pub Date : 2022-07-23 , DOI: 10.1007/s00198-022-06496-7
Amy J Koh ₁ , Hwa Kyung Nam ₂ , Megan N Michalski ₃ , Justin Do ₁ , Laurie K McCauley _{1,

4} , Nan E Hatch ₂

Affiliation

Summary

Hypophosphatasia, the rare heritable disorder caused by TNAP enzyme mutations, presents wide-ranging severity of bone hypomineralization and skeletal abnormalities. Intermittent PTH (1-34) increased long bone volume in Alpl^-/- mice but did not alter the skull phenotype. PTH may have therapeutic value for adults with TNAP deficiency–associated osteoporosis.

Introduction

Hypophosphatasia is the rare heritable disorder caused by mutations in the tissue non-specific alkaline phosphatase (TNAP) enzyme leading to TNAP deficiency. Individuals with hypophosphatasia commonly present with bone hypomineralization and skeletal abnormalities. The purpose of this study was to determine the impact of intermittent PTH on the skeletal phenotype of TNAP-deficient Alpl^-/- mice.

Methods

Alpl-/- and Alpl+/+ (wild-type; WT) littermate mice were administered PTH (1-34) (50 µg/kg) or vehicle control from days 4 to 12 and skeletal analyses were performed including gross measurements, micro-CT, histomorphometry, and serum biochemistry.

Results

Alpl^-/- mice were smaller with shorter tibial length and skull length compared to WT mice. Tibial BV/TV was reduced in Alpl^-/- mice and daily PTH (1-34) injections significantly increased BV/TV and BMD but not TMD in both WT and Alpl^-/- tibiae. Trabecular spacing was not different between genotypes and was decreased by PTH in both genotypes. Serum P1NP was unchanged while TRAcP5b was significantly lower in Alpl^-/- vs. WT mice, with no PTH effect, and no differences in osteoclast numbers. Skull height and width were increased in Alpl^-/- vs. WT mice, and PTH increased skull width in WT but not Alpl^-/- mice. Frontal skull bones in Alpl^-/- mice had decreased BV/TV, BMD, and calvarial thickness vs. WT with no significant PTH effects. Lengths of cranial base bones (basioccipital, basisphenoid, presphenoid) and lengths of synchondroses (growth plates) between the cranial base bones, plus bone of the basioccipitus, were assessed. All parameters were reduced (except lengths of synchondroses, which were increased) in Alpl^-/- vs. WT mice with no PTH effect.

Conclusion

PTH increased long bone volume in the Alpl^-/- mice but did not alter the skull phenotype. These data suggest that PTH can have long bone anabolic activity in the absence of TNAP, and that PTH may have therapeutic value for individuals with hypophosphatasia-associated osteoporosis.

中文翻译：

甲状旁腺激素在低磷酸酯酶症小鼠模型中的合成代谢作用

概括

低磷酸酯酶症是由 TNAP 酶突变引起的罕见遗传性疾病，呈现出广泛严重的骨矿化不足和骨骼异常。间歇性 PTH (1-34) 增加了Alpl ^-/-小鼠的长骨体积，但没有改变颅骨表型。PTH 可能对患有 TNAP 缺乏相关性骨质疏松症的成人具有治疗价值。

介绍

低磷酸酯酶症是一种罕见的遗传性疾病，由组织非特异性碱性磷酸酶 (TNAP) 酶突变导致 TNAP 缺乏症引起。患有低磷酸酯酶症的个体通常表现为骨矿化不足和骨骼异常。本研究的目的是确定间歇性 PTH 对 TNAP 缺陷型Alpl ^-/-小鼠骨骼表型的影响。

方法

从第 4 天到第 12 天，对Alpl-/-和Alpl+/+（野生型；WT）同窝小鼠施用 PTH (1-34) (50 µg/kg) 或载体对照，并进行骨骼分析，包括总体测量、微量CT、组织形态计量学和血清生化。

结果

与 WT 小鼠相比， Alpl ^-/-小鼠更小，胫骨长度和颅骨长度更短。Alpl ^-/-小鼠的胫骨 BV/TV 降低，每日 PTH (1-34) 注射显着增加了 WT 和Alpl ^-/-胫骨的 BV/TV 和 BMD，但不增加 TMD。小梁间距在基因型之间没有差异，并且在两种基因型中都被 PTH 降低。Alpl ^-/-与 WT 小鼠相比，血清 P1NP 没有变化，而 TRAcP5b 显着降低，没有 PTH 效应，破骨细胞数量也没有差异。与 WT 小鼠相比， Alpl ^-/-的头骨高度和宽度增加，PTH 增加了 WT 的头骨宽度，但不增加 Alpl ^-/-老鼠。与 WT 相比， Alpl ^-/-小鼠的前额颅骨降低了 BV/TV、BMD 和颅骨厚度，但没有显着的 PTH 影响。评估了颅底骨（枕骨、蝶骨、蝶骨前）的长度和颅底骨之间的同步软骨（生长板）的长度，以及基底枕骨的长度。Alpl ^-/-与无 PTH 效应的 WT 小鼠相比，所有参数都降低了（除了同步软骨的长度增加）。