The parathyroid hormone (PTH)/PTH-related peptide receptor mediates actions of both ligands in murine bone
The parathyroid hormone (PTH)/PTH-related peptide receptor mediates actions of both ligands in murine bone
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DOI：
10.1210/en.139.12.5194
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发表时间：
1998-12-01
期刊：
影响因子：
4.8
通讯作者：
Kronenberg, HM
中科院分区：
文献类型：
--
作者：
Lanske, B;Divieti, P;Kronenberg, HM
PTH和PTH相关肽（PTHrP）已被证明结合并激活相同的PTH/PTHrP受体。然而，最近的研究表明，存在针对每种配体的额外受体。我们使用PTHrP和PTH/PTHrP受体基因敲除模型来研究该受体是否介导骨中这两种配体的作用。胫骨生长板中PTHrP（-/-）和PTH/PTHrP受体（-/-）动物表型相似，提示该受体介导PTHrP的作用。电镜研究证实，两种基因型的增殖细胞和成熟细胞的细胞质中积聚了大量分散的糖原颗粒，软骨细胞分化加速，组织紊乱。然而，PTHrP（-/-）和PTH/PTHrP受体（-/-）小鼠生长板矿化模式的对比表明，PTHrP和PTH/PTHrP受体的作用并不相同。使用PTH/PTHrP受体（-/-）胚胎的颅骨进行的研究表明，该受体仅介导PTH和PTHrP刺激骨中腺苷酸环化酶和刺激骨吸收的能力。此外，我们发现PTH/PTHrP受体（-/-）动物的成骨细胞，而不是PTHrP（-/-）动物的成骨细胞，胶原酶3、骨桥蛋白和骨钙素信使rna的水平降低。因此，PTH/PTHrP受体介导PTH和PTHrP的不同生理作用。
PTH and PTH-related peptide (PTHrP) have been shown to bind to and activate the same PTH/PTHrP receptor. Recent studies have demonstrated, however, the presence of additional receptors specific for each ligand. We used the PTHrP and PTH/PTHrP receptor gene knock-out models to investigate whether this receptor mediates the actions of both ligands in bone.The similar phenotype of the PTHrP (-/-) and PTH/PTHrP receptor(-/-) animals in the growth plate of the tibia suggests that this receptor mediates the actions of PTHrP. Electron microscopic studies have confirmed the accelerated differentiation and disordered organization of chondrocytes, with the accumulation of large amounts of dispersed glycogen granules in the cytoplasm of proliferative and maturing cells of both genotypes.The contrasting growth plate mineralization patterns of the PTHrP( -/-) and PTH/PTHrP receptor(-/-) mice, however, suggest that the actions of PTHrP and the PTH/PTHrP receptor are not identical.Studies using calvariae from PTH/PTHrP receptor (-/-) embryos demonstrate that this receptor solely mediates the ability of PTH and PTHrP to stimulate adenylate cyclase in bone and to stimulate, bone resorption.Furthermore, we show that osteoblasts of PTH/PTHrP receptor (-/-) animals, but not PTHrP (-/-) animals, have decreased levels of collagenase 3, osteopontin, and osteocalcin messenger RNAs. The PTH/PTHrP receptor, therefore, mediates distinct physiologic actions of both PTH and PTHrP.