Rickets in cation-sensing receptor-deficient mice: An unexpected skeletal phenotype
Rickets in cation-sensing receptor-deficient mice: An unexpected skeletal phenotype
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DOI：
10.1210/en.142.9.3996
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发表时间：
2001-09-01
期刊：
影响因子：
4.8
通讯作者：
Quarles, LD
中科院分区：
文献类型：
--
作者：
Garner, SC;Pi, M;Quarles, LD
细胞外钙离子的局部变化可能通过细胞外阳离子感应受体(CaSR)调节成骨细胞、破骨细胞和软骨功能的假说得到了广泛的支持，但缺乏确切的证据。为了研究CaSR缺乏对骨骼的影响，我们对CaSR基因敲除小鼠(CaSR(-/-))和野生型窝仔(CaSR(+/+))的骨骼进行了详细的分析。切除CaSR(-/-)小鼠的甲状旁腺可导致甲状旁腺功能亢进、高钙血症和低磷血症。除侏儒症外，预期的甲状旁腺素过多的骨骼表现，即软骨发育不良和矿化骨形成和吸收增加，不是CaSR(-/-)小鼠的主要骨骼特征。相反，软骨病是这些动物的主要骨骼异常，表现为肥大的软骨细胞区变宽，生长板钙化受损和矿物质无序沉积，类骨质过度堆积，干骺端骨矿化滞后时间延长。在CaSR(+/+)小鼠的软骨和骨髓中检测到CaSR转录本，而在含有成熟成骨细胞和骨细胞的矿化骨中未检测到该转录本。这些发现表明，骨骼中存在钙敏感受体，它的缺失导致软骨和骨的矿化缺陷，其机制仍有待阐明。
The hypothesis that local changes in extracellular calcium may serve a physiological role in regulating osteoblast, osteoclast, and cartilage function through the extracellular cation-sensing receptor, CasR, is gaining widespread support, but lacks definite proof. To examine the effects of CasR deficiency on the skeleton, we performed a detailed analysis of the skeleton in CasR knockout mice (CasR(-/-)) and wild-type littermates (CasR(+/+)). CasR ablation in the parathyroid glands of CasR(-/-) mice resulted in hyperparathyroidism, hypercalcemia, and hypophosphatemia. Except for dwarfism, the expected skeletal manifestations of PTH excess, namely chondrodysplasia and increased mineralized bone formation and resorption, were not the main skeletal features in CasR(-/-) mice. Rather, rickets was the predominant skeletal abnormality in these animals, as evidenced by a widened zone of hypertrophic chondrocytes, impaired growth plate calcification and disorderly deposition of mineral, excessive osteoid accumulation, and prolonged mineralization lag time in metaphyseal bone. CasR transcripts were identified in cartilage and bone marrow of CasR(+/+) mice, but not in mineralized bone containing mature osteoblasts and osteocytes. These findings indicate that a calcium-sensing receptor is present in the skeleton, and its absence results in defective mineralization of cartilage and bone by mechanisms that remain to be elucidated.