Targeted ablation of the PTH/PTHrP receptor in osteocytes impairs bone structure and homeostatic calcemic responses.
Targeted ablation of the PTH/PTHrP receptor in osteocytes impairs bone structure and homeostatic calcemic responses.
复制标题
DOI：
10.1530/joe-10-0308
复制
发表时间：
2011-04
期刊：
影响因子：
--
通讯作者：
Pajevic PD
中科院分区：
文献类型：
--
作者：
Powell WF Jr;Barry KJ;Tulum I;Kobayashi T;Harris SE;Bringhurst FR;Pajevic PD
甲状旁腺激素（PTH）是钙、磷和骨骼稳态的主要生理调节剂。成骨细胞系是PTH在骨中作用的关键靶点，最近的证据表明骨细胞在PTH的合成代谢作用中可能是重要的。为了了解PTH信号通过PTH/PTHrP受体（PPR）在骨细胞中的作用，并确定这些细胞在介导激素作用中的作用，我们已经产生了在骨细胞中特异性消除PPR表达的小鼠。将其中10 Kb-Dmp 1启动子驱动他莫昔芬诱导型Cre重组酶的转基因小鼠与其中PPR外显子1侧翼为Lox-P位点的动物交配。在这些动物中，骨细胞选择性PPR敲除（Ocy-PPRcKO小鼠）可以通过他莫昔芬给药诱导。组织学分析显示Ocy-PPRcKO小鼠的骨小梁减少和轻度骨质减少。μCT分析还检测到小梁数量和厚度减少，而BV/TV%不变。这些发现与Sost和sclerostin表达的增加相关。当Ocy-PPRcKO小鼠接受低钙饮食以诱导继发性甲状旁腺功能亢进时，其血钙水平显著低于同窝对照。此外，PTH不能抑制Ocy-PPRcKO动物中的Sost和sclerostin表达，表明PTH信号传导在骨细胞中对于适当的骨重建和钙稳态的重要作用。
Parathyroid hormone (PTH) is a major physiologic regulator of calcium, phosphorous and skeletal homeostasis. Cells of the osteoblastic lineage are key targets of PTH action in bone, and recent evidence suggests that osteocytes might be important in the anabolic effects of PTH. To understand the role of PTH signaling through the PTH/PTHrP receptors (PPR) in osteocytes and to determine the role(s) of these cells in mediating the effects of the hormone, we have generated mice in which PPR expression is specifically ablated in osteocytes. Transgenic mice in which the 10Kb-Dmp1 promoter drives a tamoxifen-inducible Cre –recombinase were mated with animals in which exon1 of PPR is flanked by Lox-P sites. In these animals, osteocyte-selective PPR knockout (Ocy-PPRcKO mice) could be induced by administration of tamoxifen. Histological analysis revealed a reduction in trabecular bone and mild osteopenia in Ocy-PPRcKO mice. Reduction of trabeculae number and thickness was also detected by μCT analysis whereas BV/TV% was unchanged. These findings were associated with an increase in Sost and sclerostin expression. When Ocy-PPRcKO mice were subjected to a low calcium diet, to induce secondary hyperparathyroidism, their blood calcium levels were significantly lower than littermate controls. Moreover, PTH was unable to suppress Sost and sclerostin expression in the Ocy-PPRcKO animals, suggesting an important role of PTH signaling in osteocytes for proper bone remodeling and calcium homeostasis.