Dong Bingzi, Endo Itsuro, Ohnishi Yukiyo, Mitsui Yukari, Kurahashi Kiyoe, Kanai Mai, Hiasa Masahiro, Teramachi Jumpei, Tenshin Hirofumi, Fukumoto Seiji, Abe Masahiro, Matsumoto Toshio
Department of Hematology, Endocrinology, and Metabolism Tokushima University Graduate School of Medical Sciences Tokushima Japan.
Department of Endocrinology Affiliated Hospital of Qingdao University Qingdao China.
JBMR Plus. 2019 Mar 6;3(7):e10182. doi: 10.1002/jbm4.10182. eCollection 2019 Jul.
Activating mutations of calcium-sensing receptor (CaSR) cause autosomal dominant hypocalcemia type 1 (ADH1). Patients with ADH1 exhibit similar features to patients with hypoparathyroidism, including reduced serum parathyroid hormone (PTH) and Ca with low bone turnover. Although persistent suppression of bone turnover may increase bone fragility, bone strength in ADH1 patients has been unclear. We created knock-in mice harboring the A843E activating mutation of CaSR, mimicking severe features of ADH1 patients. The severe form of ADH1 model mice showed smaller body and bone size with lower bone mineral density (BMD) and cortical area of the femur compared with age-matched wild-type (WT) mice. Bone strength in the femur was lower in ADH1 mice even after correction by bone geometry and/or BMD. Microcracks were markedly increased in ADH1 mice, but were rarely detected in WT mice. There was a negative correlation between bone strength corrected by bone geometry and/or BMD and microcrack number or density in ADH1 and WT mice. Among ADH1 mice, negative correlation was still observed between bone strength and microcrack number or density. Microcracks increased with age in ADH1 mice, and were negatively correlated with bone strength. Treatment with PTH(1-34) or a calcilytic, JTT-305, increased bone turnover, reduced microcracks, and increased bone strength to similar levels to those in WT mice. The increase in microcracks was associated with a reduction in bone strength in ADH1 mice, and aging aggravates these changes. These results demonstrate that activating mutation of CaSR causes reduction in PTH secretion with suppressed bone turnover, that reduced bone turnover is associated with an age-dependent increase in microcracks with a reduction in bone strength, and that both PTH(1-34) and calcilytic ameliorate all these changes in bone turnover and strength. It is suggested that fracture susceptibility may be increased in severe types of ADH1 patients especially in the elderly. © 2019 The Authors. published by Wiley Periodicals, Inc. on behalf of American Society for Bone and Mineral Research.
钙敏感受体（CaSR）的激活突变会导致1型常染色体显性低钙血症（ADH1）。ADH1患者表现出与甲状旁腺功能减退患者相似的特征，包括血清甲状旁腺激素（PTH）降低、血钙降低以及骨转换率低。尽管骨转换的持续抑制可能会增加骨脆性，但ADH1患者的骨强度尚不清楚。我们构建了携带CaSR A843E激活突变的基因敲入小鼠，模拟ADH1患者的严重特征。与年龄匹配的野生型（WT）小鼠相比，严重型ADH1模型小鼠的体型和骨骼尺寸更小，股骨的骨矿物质密度（BMD）和皮质面积更低。即使通过骨几何形状和/或BMD进行校正后，ADH1小鼠股骨的骨强度仍较低。ADH1小鼠的微裂纹明显增加，但在WT小鼠中很少检测到。在ADH1和WT小鼠中，经骨几何形状和/或BMD校正后的骨强度与微裂纹数量或密度之间呈负相关。在ADH1小鼠中，骨强度与微裂纹数量或密度之间仍呈负相关。ADH1小鼠的微裂纹随年龄增加，且与骨强度呈负相关。用甲状旁腺激素（1-34）或钙敏感受体拮抗剂JTT-305治疗可增加骨转换，减少微裂纹，并将骨强度提高到与WT小鼠相似的水平。微裂纹的增加与ADH1小鼠骨强度的降低有关，并且衰老会加剧这些变化。这些结果表明，CaSR的激活突变导致PTH分泌减少，骨转换受到抑制，骨转换减少与微裂纹随年龄增加以及骨强度降低有关，并且甲状旁腺激素（1-34）和钙敏感受体拮抗剂均可改善骨转换和强度的所有这些变化。提示严重型ADH1患者尤其是老年人的骨折易感性可能会增加。©2019作者。由Wiley Periodicals, Inc.代表美国骨与矿物质研究学会出版。
