Department of Oral Health and Diagnostic Sciences, School of Dental Medicine, University of Connecticut Health, Farmington, CT, USA.
Institute of Enzymology, Research Center for Natural Sciences, Hungarian Academy of Sciences Centre of Excellence, Budapest, Hungary.
J Bone Miner Res. 2020 Oct;35(10):2070-2081. doi: 10.1002/jbmr.4110. Epub 2020 Jul 12.
Craniometaphyseal dysplasia (CMD), a rare genetic bone disorder, is characterized by lifelong progressive thickening of craniofacial bones and metaphyseal flaring of long bones. The autosomal dominant form of CMD is caused by mutations in the progressive ankylosis gene ANKH (mouse ortholog Ank), encoding a pyrophosphate (PPi) transporter. We previously reported reduced formation and function of osteoblasts and osteoclasts in a knockin (KI) mouse model for CMD (Ank) and in CMD patients. We also showed rapid protein degradation of mutant ANK/ANKH. Mutant ANK protein displays reduced PPi transport, which may alter the inorganic phosphate (Pi) and PPi ratio, an important regulatory mechanism for bone mineralization. Here we investigate whether reducing dietary Pi intake can ameliorate the CMD-like skeletal phenotype by comparing male and female Ank and Ank mice exposed to a low (0.3%) and normal (0.7%) Pi diet for 13 weeks from birth. Serum Pi and calcium (Ca) levels were not significantly changed by diet, whereas PTH and 25-hydroxy vitamin D (25-OHD) were decreased by low Pi diet but only in male Ank mice. Importantly, the 0.3% Pi diet significantly ameliorated mandibular hyperostosis in both sexes of Ank mice. A tendency of decreased femoral trabeculation was observed in male and female Ank mice as well as in male Ank mice fed with the 0.3% Pi diet. In contrast, in female Ank mice the 0.3% Pi diet resulted in increased metaphyseal trabeculation. This was also the only group that showed increased bone formation rate. Low Pi diet led to increased osteoclast numbers and increased bone resorption in all mice. We conclude that lowering but not depleting dietary Pi delays the development of craniofacial hyperostosis in CMD mice without severely compromising serum levels of Pi, Ca, PTH, and 25-OHD. These findings may have implications for better clinical care of patients with CMD. © 2020 American Society for Bone and Mineral Research.
颅骨-干骺端发育不良（CMD）是一种罕见的遗传性骨骼疾病，其特征为终生进行性颅面骨增厚和长骨干骺端增宽。CMD 的常染色体显性形式是由渐进性强直基因 ANKH（小鼠同源物 Ank）的突变引起的，ANKH 编码焦磷酸（PPi）转运蛋白。我们之前报道过 CMD（ANK）敲入（KI）小鼠模型和 CMD 患者中破骨细胞和成骨细胞的形成和功能降低。我们还显示突变型 ANK/ANKH 的快速蛋白降解。突变型 ANK 蛋白显示 PPi 转运减少，这可能改变无机磷（Pi）和 PPi 比值，这是骨骼矿化的重要调节机制。在这里，我们通过比较雄性和雌性 Ank 和 Ank 小鼠从出生开始分别在低（0.3%）和正常（0.7%）磷饮食中摄入 13 周，来研究减少饮食中磷的摄入是否可以改善 CMD 样骨骼表型。血清 Pi 和钙（Ca）水平不受饮食影响，但低磷饮食降低了甲状旁腺激素（PTH）和 25-羟维生素 D（25-OHD），但仅在雄性 Ank 小鼠中。重要的是，0.3%Pi 饮食显著改善了雄性和雌性 Ank 小鼠的下颌骨骨增生。观察到雄性和雌性 Ank 小鼠以及雄性 Ank 小鼠的股骨小梁减少，0.3%Pi 饮食也有这种趋势。相反，在雌性 Ank 小鼠中，0.3%Pi 饮食导致骺板骨小梁增加。这也是唯一显示骨形成率增加的组。低磷饮食导致所有小鼠的破骨细胞数量增加和骨吸收增加。我们得出结论，降低但不耗尽饮食中的磷可延迟 CMD 小鼠颅面骨过度增生的发展，而不会严重影响血清 Pi、Ca、PTH 和 25-OHD 的水平。这些发现可能对改善 CMD 患者的临床护理具有重要意义。
