Chang Wenhan, Dvorak Melita, Shoback Dolores
Endocrine Research Unit, Department of Veterans Affairs Medical Center, Department of Medicine,University of California, San Francisco, California, USA.
Methods Enzymol. 2010;484:253-66. doi: 10.1016/B978-0-12-381298-8.00013-7.
Constitutive activity of the extracellular calcium-sensing receptor (CaSR) has been studied in kindreds with the human disorder autosomal dominant hypocalcemia (ADH) and in an animal model called the Nuf mouse. These families generally showed reduced parathyroid hormone (PTH) secretion and excessive renal calcium (Ca(2+)) excretion. Soft tissues calcifications in the kidney and basal ganglia are frequent (10-50% of ADH cases), and there is a single report of skeletal abnormalities in a family resulting in short stature and premature osteoarthritis. In the latter, a causative mechanism could not be determined. The phenotype of the Nuf mouse is one of ectopic calcifications and cataracts in addition to biochemical abnormalities (low serum Ca(2+) and high serum phosphate concentrations). To better understand the role of CaSRs in the control of osteoblastic function, we generated a transgenic mouse model with constitutively active CaSRs in mature osteoblasts. An analysis of the skeletal phenotype of that mouse indicates that strong signaling by CaSRs in this cell lineage induces alterations in the bone homeostasis reflected in mild osteopenia in male and female mice during growth and in adulthood. These studies indicate that this approach can be readily adapted to assess CaSR actions in other cell systems.
细胞外钙敏感受体（CaSR）的组成性活性已在患有常染色体显性低钙血症（ADH）的人类家系以及一种名为Nuf小鼠的动物模型中进行了研究。这些家系通常表现出甲状旁腺激素（PTH）分泌减少和肾脏钙（Ca²⁺）排泄过多。肾脏和基底神经节的软组织钙化很常见（ADH病例的10 - 50%），并且有一份关于一个家系骨骼异常导致身材矮小和过早出现骨关节炎的报告。在后者中，无法确定致病机制。Nuf小鼠的表型除了生化异常（低血清Ca²⁺和高血清磷酸盐浓度）外，还包括异位钙化和白内障。为了更好地理解CaSR在控制成骨细胞功能中的作用，我们构建了一种在成熟成骨细胞中具有组成性活性CaSR的转基因小鼠模型。对该小鼠骨骼表型的分析表明，该细胞系中CaSR的强信号传导会诱导骨稳态改变，表现为雄性和雌性小鼠在生长和成年期出现轻度骨质减少。这些研究表明，这种方法可以很容易地用于评估CaSR在其他细胞系统中的作用。
