Endocrine Research Unit, Department of Veterans Affairs Medical Center, Department of Medicine, University of California, San Francisco, CA, USA.
J Bone Miner Res. 2013 May;28(5):1087-100. doi: 10.1002/jbmr.1846.
We studied mice with or without heterozygous deletion of the Casr in the parathyroid gland (PTG) [(PTG) CaSR(+/-)] to delineate effects of age and sex on manifestations of hyperparathyroidism (HPT). In control mice, aging induced a left-shift in the Ca(2+) /parathyroid hormone (PTH) set point accompanied by increased PTG CaSR expression along with lowered serum Ca(2+) and mildly increased PTH levels, suggesting adaptive responses of PTGs to aging-induced changes in mineral homeostasis. The aging effects on Ca(2+) /PTH set point and CaSR expression were significantly blunted in (PTG) CaSR(+/-) mice, who showed instead progressively elevated PTH levels with age, especially in 12-month-old females. These 12-month-old knockout mice demonstrated resistance to their high PTH levels in that serum 1,25-dihydroxyvitamin D (1,25-D) levels and RNA expression of renal Cyp27b1 and expression of genes involved in Ca(2+) transport in kidney and intestine were unresponsive to the rising PTH levels. Such changes may promote negative Ca(2+) balance, which further exacerbate the HPT. Skeletal responses to HPT were age-, sex-, and site-dependent. In control mice of either sex, trabecular bone in the distal femur decreased whereas cortical bone in the tibiofibular junction increased with age. In male (PTG) CaSR(+/-) mice, anabolic actions of the elevated PTH levels seemed to protect against trabecular bone loss at ≥ 3 months of age at the expense of cortical bone loss. In contrast, HPT produced catabolic effects on trabecular bone and anabolic effects on cortical bone in 3-month-old females; but these effects reversed by 12 months, preserving trabecular bone in aging mice. We demonstrate that the CaSR plays a central role in the adaptive responses of parathyroid function to age-induced changes in mineral metabolism and in target organ responses to calciotropic hormones. Restraining the ability of the PTG to upregulate CaSRs by heterozygous gene deletion contributes to biochemical and skeletal manifestations of HPT, especially in aging females.
我们研究了甲状旁腺（PTG）中 Casr 杂合缺失的 Casr 敲除小鼠[(PTG) CaSR(+/-)]，以阐明年龄和性别对甲状旁腺功能亢进（HPT）表现的影响。在对照小鼠中，衰老引起 Ca(2+) /甲状旁腺激素（PTH）设定点左移，同时伴有 PTG CaSR 表达增加，血清 Ca(2+)降低，PTH 水平轻度升高，提示 PTG 对衰老引起的矿物质稳态变化的适应性反应。在（PTG） CaSR(+/-) 小鼠中，衰老对 Ca(2+) /PTH 设定点和 CaSR 表达的影响明显减弱，这些小鼠随着年龄的增长，PTH 水平逐渐升高，尤其是 12 月龄雌性小鼠。这些 12 月龄的敲除小鼠对其高 PTH 水平表现出抵抗力，即血清 1,25-二羟维生素 D（1,25-D）水平和肾脏 Cyp27b1 的 RNA 表达以及肾脏和肠道中参与 Ca(2+) 转运的基因的表达对升高的 PTH 水平没有反应。这些变化可能会促进负钙平衡，从而进一步加重 HPT。HPT 的骨骼反应取决于年龄、性别和部位。在任何性别的对照小鼠中，远端股骨的小梁骨减少，而胫腓骨交界处的皮质骨增加随着年龄的增长。在雄性（PTG） CaSR(+/-) 小鼠中，升高的 PTH 水平的合成代谢作用似乎保护了至少 3 个月大的小鼠的小梁骨免受丢失，代价是皮质骨丢失。相比之下，HPT 在 3 月龄雌性小鼠中对小梁骨产生分解代谢作用，对皮质骨产生合成代谢作用；但这些作用在 12 个月时逆转，在衰老小鼠中保留了小梁骨。我们证明 CaSR 在甲状旁腺功能对矿物质代谢年龄相关变化的适应性反应以及钙调节激素对靶器官的反应中起核心作用。通过杂合基因缺失抑制 PTG 上调 CaSR 的能力有助于 HPT 的生化和骨骼表现，尤其是在衰老的雌性中。
