Ablation of the PTHrP gene or the PTH/PTHrP receptor gene leads to distinct abnormalities in bone development
Ablation of the PTHrP gene or the PTH/PTHrP receptor gene leads to distinct abnormalities in bone development
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DOI：
10.1172/jci6629
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发表时间：
1999-08-01
影响因子：
15.9
通讯作者：
Kronenberg, HM
中科院分区：
文献类型：
--
作者：
Lanske, B;Amling, M;Kronenberg, HM
甲状旁腺激素（PTH）和甲状旁腺激素相关肽（PTHrP）结合并激活相同的PTH/PTHrP受体。PTHrP基因或PTH/PTHrP受体基因的缺失都会导致生长板软骨细胞分化加速。为了进一步探讨PTHrP与PTH/PTHrP受体的功能关系，我们分析了基因敲除小鼠发育早期的骨骼，并对双基因敲除小鼠的表型进行了表征。两种基因敲除共有一种早期表型。正常情况下，第一个变肥大的软骨细胞位于长骨的中心；这种极性在这两种淘汰中都大大减弱了。PTH/PTHrP受体缺陷（PTH/PTHrP- r- /-）小鼠表现出PTHrP（-/-）小鼠所不具有的2种独特表型。在长骨轴的膜内骨形成过程中，只有PTH/PTHrP-R-/-骨表现出成骨细胞数量和基质积累的显著增加。此外，PTH/PTHrP-R-/-小鼠显示原发性海绵状软骨的骨小梁形成显著减少，早期软骨模型的血管侵袭延迟。在双纯合子敲除小鼠中，血管侵袭没有发生延迟。因此，PTHrP必须通过一种独立于PTH/PTHrP受体的机制来减缓血管入侵。
Parathyroid hormone (PTH) and parathyroid hormone-related peptide (PTHrP) bind to and activate the same PTH/PTHrP receptor. Deletion of either the PTHrP gene or the PTH/PTHrP receptor gene leads to acceleration of differentiation of growth plate chondrocytes. To explore further the functional relationships of PTHrP and the PTH/PTHrP receptor, bones of knockout mice were analyzed early in development, and the phenotypes of double-knockout mice were characterized.One early phenotype is shared by both knockouts. Normally, the first chondrocytes to become hypertrophic are located in the centers of long bones; this polarity is greatly diminished in both these knockouts. The PTH/PTHrP receptor-deficient (PTH/PTHrP-R-/-) mice exhibited 2 unique phenotypes not shared by the PTHrP(-/-) mice. During intramembranous bone formation in the shafts of long bones, only the PTH/PTHrP-R-/- bones exhibit a striking increase in osteoblast number and matrix accumulation. Furthermore, the PTH/PTHrP-R-/- mice showed a dramatic decrease in trabecular bone formation in the primary spongiosa and a delay in vascular invasion of the early cartilage model. In the double-homozygous knockout mice, the delay in vascular invasion did not occur. Thus, PTHrP must slow vascular invasion by a mechanism independent of the PTH/PTHrP receptor.