Department of Periodontology and Oral Medicine, School of Dentistry, University of Michigan, Ann Arbor, MI, USA.
Department of Orthodontics and Pediatric Dentistry, School of Dentistry, University of Michigan, Ann Arbor, MI, USA.
Osteoporos Int. 2022 Nov;33(11):2423-2433. doi: 10.1007/s00198-022-06496-7. Epub 2022 Jul 23.
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.
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.
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.
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.
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.
低磷酸酯酶症是一种罕见的遗传性疾病，由 TNAP 酶基因突变引起，表现为广泛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 对 TNAP 缺乏相关骨质疏松症的成年人可能具有治疗价值。
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）酶基因突变导致 TNAP 缺乏引起。低磷酸酯酶症患者常出现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 Alpl 小鼠骨骼表型的影响。
从第 4 天到第 12 天，给 Alpl-/-和 Alpl+/+（野生型；WT）同窝仔鼠施用 PTH（1-34）（50μg/kg）或载体对照，并进行骨骼分析，包括大体测量、微 CT、组织形态计量学和血清生化分析。
Alpl 小鼠比 WT 小鼠体型小，胫骨长度和颅骨长度较短。Alpl 小鼠的胫骨 BV/TV 减少，每日 PTH（1-34）注射显著增加了 WT 和 Alpl 胫骨的 BV/TV 和 BMD，但不增加 TMD。骨小梁间距在基因型之间没有差异，两种基因型的 PTH 均降低了骨小梁间距。血清 P1NP 没有变化，而 Alpl 与 WT 小鼠相比，TRAcP5b 显著降低，无 PTH 作用，破骨细胞数量无差异。Alpl 与 WT 小鼠相比，颅骨高度和宽度增加，WT 小鼠的颅骨宽度在 PTH 作用下增加，而 Alpl 小鼠则没有。Alpl 小鼠的颅骨骨小梁 BV/TV、BMD 和颅骨厚度均低于 WT 小鼠，无明显的 PTH 作用。评估了颅底骨（基枕骨、基蝶骨、前蝶骨）和颅底骨之间的软骨结合（生长板）的长度，以及基枕骨的骨长度。Alpl 与 WT 小鼠相比，所有参数均降低（除了软骨结合的长度增加），无 PTH 作用。
PTH 增加了 Alpl 小鼠的长骨体积，但没有改变颅骨表型。这些数据表明，PTH 可以在没有 TNAP 的情况下发挥长骨合成代谢活性，PTH 对低磷酸酯酶症相关骨质疏松症的个体可能具有治疗价值。
