Role of parathyroid hormone-related peptide and Indian hedgehog in skeletal development
Role of parathyroid hormone-related peptide and Indian hedgehog in skeletal development
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DOI：
10.1007/s004670000343
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发表时间：
2000-07-01
影响因子：
3
通讯作者：
Jüppner, H
中科院分区：
文献类型：
--
作者：
Jüppner, H
甲状旁腺激素相关肽(PTHrP)是一种通过PTH/PTHrP受体(PTH1R)调节软骨细胞增殖和分化的自分泌/旁分泌调节因子，常引起恶性综合征的体液高钙血症。PTHrP是对印度刺猬(IHH)的反应而产生的，IHH通过修补的膜受体介导其作用，但也与刺猬相互作用蛋白(HIP)相互作用。缺乏PTHrP的小鼠表现出软骨细胞加速分化，因此通过软骨内过程形成的骨骼过早成骨，PTH1R消融的动物也观察到类似但更严重的异常。这些骨骼发现的镜像，即软骨细胞分化和软骨内成骨的严重延迟，在α1(II)前胶原启动子控制下过表达PTHrP的转基因小鼠中观察到。在人类的两种遗传疾病中也观察到软骨细胞增殖和分化的严重异常，这两种疾病很可能是由PTH1R突变引起的。在Jansen干骺端软骨发育不良患者中发现了导致结构性活性的PTH1R杂合性突变，在Blomstrand致死性软骨发育不良患者中发现了导致受体活性降低或完全无效的纯合子或复合杂合性突变。根据在这些人类疾病和PTHrP或PTH1R异常表达的小鼠中观察到的生长板异常，似乎PTHrP和/或其受体的表达受损与终末期肾病儿童的生长异常有关。事实上，在动物中，轻到中度的肾功能衰竭会导致生长板中PTH1R的表达减少，并损害生长，但目前仍不确定这是否有助于改变软骨细胞的生长和分化。
Parathyroid hormone-related peptide (PTHrP), which frequently causes the humoral hypercalcemia of malignancy syndrome, is an autocrine/paracrine regulator of chondrocyte proliferation and differentiation that acts through the PTH/PTHrP receptor (PTH1R). PTHrP is generated in response to Indian hedgehog (Ihh), which mediates its actions through the membrane receptor patched, but interacts also with hedgehog-interacting protein (Hip). Mice lacking PTHrP show accelerated chondrocyte differentiation, and thus premature ossification of those bones that are formed through an endochondral process, and similar but more-severe abnormalities are observed in PTH1R-ablated animals. The mirror image of these skeletal findings, i.e., a severe delay in chondrocyte differentiation and endochondral ossification, is observed in transgenic mice that overexpress PTHrP under the control of the alpha 1(II) procollagen promoter. Severe abnormalities in chondrocyte proliferation and differentiation are also observed in two genetic disorders in humans that are most likely caused by mutations in the PTH1R. Heterozygous PTH1R mutations that lead to constitutively activity were identified in Jansen metaphyseal chondrodysplasia, and homozygous or compound heterozygous mutations that lead to less-active or completely inactive receptors were identified in patients with Blomstrand lethal chondrodysplasia. Based on the growth plate abnormalities observed in these human disorders and in mice with abnormal expression of either PTHrP or the PTH1R, it appears plausible that impaired expression of PTHrP and/or its receptor contributes to the growth abnormalities in children with end-stage renal disease. In fact, mild-to-moderate renal failure leads in animals to a reduction in PTH1R expression in growth plates and impaired growth, but it remains uncertain whether this contributes to altered chondrocyte growth and differentiation.