Targeted expression of constitutively active receptors for parathyroid hormone and parathyroid hormone-related peptide delays endochondral bone formation and rescues mice that lack parathyroid hormone-related peptide
Targeted expression of constitutively active receptors for parathyroid hormone and parathyroid hormone-related peptide delays endochondral bone formation and rescues mice that lack parathyroid hormone-related peptide
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DOI：
10.1073/pnas.94.25.13689
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发表时间：
1997-12-09
影响因子：
11.1
通讯作者：
Juppner, H
中科院分区：
文献类型：
--
作者：
Schipani, E;Lanske, B;Juppner, H
编码甲状旁腺激素（PTH）相关肽（PTHrP）或PTH/PTHrP受体的基因已被同源重组消除的小鼠，由于软骨内骨形成加速而表现出骨骼发育不良，并分别在出生时或子宫内死亡。在 PTHrP 表达针对生长板的转基因小鼠以及 Jansen 干骺端软骨发育不良（一种由持续活跃的 PTH/PTHrP 受体引起的罕见遗传性疾病）患者中观察到由于软骨细胞成熟减慢导致的骨骼异常。因此，这些和其他发现表明 PTHrP 及其受体对于软骨细胞分化至关重要。为了进一步探索 PTH/PTHrP 受体在此过程中的作用，我们培育了转基因小鼠，其中组成型活性受体 HKrk-H223R 的表达通过大鼠 α 1 (LT) 胶原蛋白启动子靶向生长板。追求两个主要目标：（i）研究组成型活性 PTH/PTHrP 受体如何影响软骨细胞成熟程序； (ii) 确定突变受体的表达是否会纠正 PTHrP 消融小鼠 (PTHrP-/-) 的严重生长板异常。组成型活性 PTH/PTHrP 受体的靶向表达导致矿化延迟，增殖软骨细胞向软骨内过程形成的骨骼节段中肥大细胞的转化减慢，以及肥大软骨细胞长期存在并延迟血管侵袭。此外，它还纠正了 PTHrP-/- 小鼠出生时的生长板异常，并延长了它们的生存期。 “获救”的动物没有牙齿萌出，骨骺过早闭合，表明这两个过程都涉及 PTHrP。这些发现表明，获救的 PTHrP-/-小鼠 mag 对于研究 PTHrP 在出生后发育中的多种可能具有组织特异性的作用具有相当重要的意义。
Mice in which the genes encoding the parathyroid hormone (PTH)-related peptide (PTHrP) or the PTH/PTHrP receptor have been ablated by homologous recombination show skeletal dysplasia due to accelerated endochondral bone formation, and die at birth or in utero, respectively. Skeletal abnormalities due to decelerated chondrocyte maturation are observed in transgenic mice where PTHrP expression is targeted to the growth plate, and in patients with Jansen metaphyseal chondrodysplasia, a rare genetic disorder caused by constitutively active PTH/PTHrP receptors. These and other findings thus indicate that PTHrP and its receptor are essential for chondrocyte differentiation. To further explore the role of the PTH/PTHrP receptor in this process,,ve generated transgenic mice in which expression of a constitutively active receptor, HKrk-H223R, was targeted to the growth plate by the rat alpha 1 (LT) collagen promoter. Two major goals were pursued: (i) to investigate how constitutively active PTH/PTHrP receptors affect the program of chondrocyte maturation; and (ii) to determine whether expression of the mutant receptor would correct the severe growth plate abnormalities of PTHrP-ablated mice (PTHrP-/-). The targeted expression of constitutively active PTH/PTHrP receptors led to delayed mineralization, decelerated conversion of proliferative chondrocytes into hypertrophic cells in skeletal segments that are formed by the endochondral process, and prolonged presence of hypertrophic chondrocytes with delay of vascular invasion. Furthermore, it corrected at birth the growth plate abnormalities of PTHrP-/-mice and allowed their prolonged survival. ''Rescued'' animals lacked tooth eruption and showed premature epiphyseal closure, indicating that both processes involve PTHrP. These findings suggest that rescued PTHrP-/-mice mag gain considerable importance for studying the diverse, possibly tissue-specific role(s) of PTHrP in postnatal development.