Unsuspected osteochondroma-like outgrowths in the cranial base of Hereditary Multiple Exostoses patients and modeling and treatment with a BMP antagonist in mice
Unsuspected osteochondroma-like outgrowths in the cranial base of Hereditary Multiple Exostoses patients and modeling and treatment with a BMP antagonist in mice
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DOI：
10.1371/journal.pgen.1006742
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发表时间：
2017-04-01
期刊：
影响因子：
4.5
通讯作者：
Pacifici, Maurizio
中科院分区：
文献类型：
--
作者：
Sinha, Sayantani;Mundy, Christina;Pacifici, Maurizio
遗传性多发性外生骨疣（HME）是一种罕见的儿科疾病，由硫酸乙酰肝素（HS）合成酶EXT 1或EXT 2编码基因的功能缺失突变引起。HME的特征是在许多轴向和非轴向骨骼元件的生长板附近形成软骨副产物-称为骨软骨瘤。令人惊讶的是，目前还不知道这种肿瘤是否也形成于颅面骨骼的软骨内成分。在这里，我们对50例连续HME患者的颈椎MRI和CT扫描进行了回顾性分析，包括颅骨骨骼图像。有趣的是，近一半的患者在颅底，特别是在斜坡显示中度缺损或骨软骨瘤样生长。在良好的相关性中，骨软骨瘤在突变Ext 1（f/f）; Col 2-CreER或Ext 1（f/f）;聚集蛋白聚糖-CreER小鼠模型的颅底中沿着软骨结合生长板发展。骨软骨瘤形成之前，在软骨软骨膜边界的细胞表型改变，并伴随着异位表达的主要软骨基质基因-胶原2和胶原X-内的异位增长的群众。由于软骨形成需要骨形态发生蛋白（BMP）信号，我们询问骨软骨瘤的形成是否可以被BMP信号拮抗剂阻断。LDN-193189全身给药可有效抑制条件性Ext 1突变小鼠的骨软骨瘤生长。小鼠胚胎软骨形成细胞的体外研究阐明了LDN-193189作用的机制，结果包括典型BMP信号传导pSMAD 1/5/8效应物的减少，但有趣的是，同时增加了pERK 1/2和Chordin，Fgf 9和Fgf 18表达等抗软骨形成机制。我们的研究首次揭示了HME患者的颅底可能受到影响，并且骨软骨瘤的形成可以接受治疗药物干预。
Hereditary Multiple Exostoses (HME) is a rare pediatric disorder caused by loss-of-function mutations in the genes encoding the heparan sulfate (HS)-synthesizing enzymes EXT1 or EXT2. HME is characterized by formation of cartilaginous outgrowths-called osteochondromas- next to the growth plates of many axial and appendicular skeletal elements. Surprisingly, it is not known whether such tumors also form in endochondral elements of the craniofacial skeleton. Here, we carried out a retrospective analysis of cervical spine MRI and CT scans from 50 consecutive HME patients that included cranial skeletal images. Interestingly, nearly half of the patients displayed moderate defects or osteochondroma-like outgrowths in the cranial base and specifically in the clivus. In good correlation, osteochondromas developed in the cranial base of mutant Ext1(f/f);Col2-CreER or Ext1(f/f);Aggrecan-CreER mouse models of HME along the synchondrosis growth plates. Osteochondroma formation was preceded by phenotypic alteration of cells at the chondro-perichondrial boundary and was accompanied by ectopic expression of major cartilage matrix genes -collagen 2 and collagen X-within the growing ectopic masses. Because chondrogenesis requires bone morphogenetic protein (BMP) signaling, we asked whether osteochondroma formation could be blocked by a BMP signaling antagonist. Systemic administration with LDN-193189 effectively inhibited osteochondroma growth in conditional Ext1-mutant mice. In vitro studies with mouse embryo chondrogenic cells clarified the mechanisms of LDN-193189 action that turned out to include decreases in canonical BMP signaling pSMAD1/5/8 effectors but interestingly, concurrent increases in such anti-chondrogenic mechanisms as pERK1/2 and Chordin, Fgf9 and Fgf18 expression. Our study is the first to reveal that the cranial base can be affected in patients with HME and that osteochondroma formation is amenable to therapeutic drug intervention.