A mutant PTH/PTHrP type I receptor in enchondromatosis
A mutant PTH/PTHrP type I receptor in enchondromatosis
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DOI：
10.1038/ng844
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发表时间：
2002-03-01
期刊：
影响因子：
30.8
通讯作者：
Alman, BA
中科院分区：
文献类型：
--
作者：
Hopyan, S;Gokgoz, N;Alman, BA
内生软骨瘤是一种常见的良性骨软骨肿瘤。在内生软骨瘤病（Ollier和Maffucci病）中，它们可以作为孤立性病变或作为多发性病变发生。内生软骨瘤引起的临床问题包括骨骼畸形和恶性转化为软骨肉瘤的可能性（1-3）。内生软骨瘤病累及骨骼的程度是可变的，可能包括不直接归因于内生软骨瘤的发育异常[4]。内生软骨瘤病是罕见的，明显的遗传条件是不寻常的，没有候选位点已被确定。内生软骨瘤通常与生长板软骨紧密相连。因此，它们可能是由邻近生长板中软骨细胞增殖和终末分化的异常调节引起的。在正常生长板中，增殖软骨细胞向有丝分裂后肥大软骨细胞的分化部分受到涉及甲状旁腺激素相关蛋白（PTHrP）和印度刺猬（IHH）的紧偶联信号传递的调节（5-9）。PTHrP延迟增殖软骨细胞的肥大分化，而IHH促进软骨细胞增殖。我们发现了一种突变的PTH/PTHrP I型受体（PTHR 1）在人内生软骨瘤病，在体外信号异常，并导致内生软骨瘤样病变的转基因小鼠。突变体受体组成型激活Hedgehog信号传导，并且过量的Hedgehog信号传导足以引起内生软骨瘤样病变的形成。
Enchondromas are common benign cartilage tumors of bone. They can occur as solitary lesions or as multiple lesions in enchondromatosis (Ollier and Maffucci diseases). Clinical problems caused by enchondromas include skeletal deformity and the potential for malignant change to chondrosarcoma(1-3). The extent of skeletal involvement is variable in enchondromatosis and may include dysplasia that is not directly attributable to enchondromas(4). Enchondromatosis is rare, obvious inheritance of the condition is unusual and no candidate loci have been identified. Enchondromas are usually in close proximity to, or in continuity with, growth-plate cartilage. Consequently, they may result from abnormal regulation of proliferation and terminal differentiation of chondrocytes in the adjoining growth plate. In normal growth plates, differentiation of proliferative chondrocytes to post-mitotic hypertrophic chondrocytes is regulated in part by a tightly coupled signaling relay involving parathyroid hormone related protein (PTHrP) and Indian hedgehog (IHH)(5-9). PTHrP delays the hypertrophic differentiation of proliferating chondrocytes, whereas IHH promotes chondrocyte proliferation. We identified a mutant PTH/PTHrP type I receptor (PTHR1) in human enchondromatosis that signals abnormally in vitro and causes enchondroma-like lesions in transgenic mice. The mutant receptor constitutively activates Hedgehog signaling, and excessive Hedgehog signaling is sufficient to cause formation of enchondroma-like lesions.