Pathogenic Mechanisms in Hereditary Multiple Exostoses Syndrome

遗传性多发性骨软骨病(HME)是一种罕见的常染色体显性遗传性疾病，影响数千名儿童 全世界。HME的特征是软骨-骨肿瘤，称为骨软骨瘤，形成于 软骨膜沿生长板突出并与周围组织碰撞。肿瘤可以 从而导致骨骼畸形、神经血管受压和慢性疼痛，并成为 大约2%-3%的患者是恶性的。目前的治疗方法是有限的，患者与疼痛和有限的 行动不便，一生中要接受多次手术。大多数HME患者携带一种杂合性突变 负责硫酸乙酰肝素(HS)合成的EXT1或EXT2，从而导致部分全身性HS 缺乏症。HS链--以及它们所在的蛋白多糖--调节和明显地调节 很多过程。值得注意的是，它们与包括骨形态发生蛋白(BMPs)在内的信号蛋白相互作用 和刺猬家族成员，通常限制和界定蛋白质的分布、可获得性和 活动。然而，目前还不清楚这些机制中的哪些机制是否可能在HME中错乱，以及它是如何错乱的 可能会导致肿瘤的形成。在之前的资助期间，我们发现有条件地消融Ext1 导致软骨膜中促软骨性BMP信号的增加，同时抗-BMP信号的降低 软骨性pERK1/2和Noggin，扰乱正常维持 软骨膜表型。在初步研究中，我们的目标是阐明骨软骨瘤是如何获得 生长板状组织能够在周围组织的作用下单向生长，从而形成 破坏和破坏。我们已经获得了建立IHH-PTHrP轴驱动肿瘤的证据 外延生长。我们的中心假设是骨软骨瘤的发展和生长是由以下因素驱动的：(I)a HS局部严重缺乏；(Ii)BMP信号增加；(Iii)NEO IHH-PTHrP环路的建立。AS 因此，我们假设骨软骨瘤的发展和生长可以通过药物治疗来实现。 针对这些调节电路的组件。我们将使用遗传、生化和细胞方法，并 接近模拟人类疾病进展和负担的转基因小鼠模型。该项目将继续进行 为肿瘤形成的细胞和分子机制以及 这些机制在标准的软骨膜和生长板细胞中正常运作。它还将测试 基于这些见解的可能的治疗方法，因此具有重大的转化医学价值和影响。 HME患者数量相对较少，但其家庭所在社区较大。这个项目将 从而给患者和家属带来了新的希望，即这种疾病将继续活跃 经过研究，有一天可能会找到治愈的方法。

Hereditary Multiple Exostoses (HME) is a rare autosomal dominant disorder that affects thousands of children worldwide. HME is characterized by cartilaginous-bony tumors called osteochondromas that form within perichondrium along growth plates and protrude into and collide with surrounding tissues. The tumors can thus cause skeletal deformities, compression of nerves and blood vessels and chronic pain, and become malignant in about 2-3% of patients. Current therapies are limited, and patients struggle with pain and limited mobility and undergo multiple surgeries through life. Most HME patients bear a heterozygous mutation in EXT1 or EXT2 that are responsible for heparan sulfate (HS) synthesis, thus causing a partial systemic HS deficiency. The HS chains -and the proteoglycans of which they are part- regulate and distinctly modulate many processes. Notably, they interact with signaling proteins including bone morphogenetic proteins (BMPs) and hedgehog family members and most often restrict and delimit protein distribution, availability and activity. However, it is not clear whether and which of these mechanisms may be deranged in HME and how it could lead to tumor formation. In the previous funding period, we found that conditional ablation of Ext1 caused an increase in pro-chondrogenic BMP signaling in perichondrium and a concurrent decrease in anti- chondrogenic pERK1/2 and Noggin, deranging normal homeostatic mechanisms that normally maintain the perichondrium phenotype. In preliminary studies, we have aimed to clarify how the osteochondromas acquire a growth plate-like organization, are able to grow unidirectionally against surrounding tissues and thus create damage and havoc. We have obtained evidence for the establishment of an IHH-PTHrP axis driving tumor outgrowth. Our central hypotheses is that osteochondroma development and outgrowth are driven by: (i) a steep local deficiency in HS; (ii) increased BMP signaling; and (iii) establishment of a neo IHH-PTHrP loop. As a result, we posit that osteochondroma development and growth are amenable to drug treatments directed against components of those regulatory circuits. We will use genetic, biochemical and cellular approaches and transgenic mouse models that closely mimic human disease progression and burden. The project will continue to provide fundamentally new insights into cellular and molecular mechanisms of tumor formation as well as normal functioning of those mechanisms in standard perichondrial and growth plate cells. It will also test possible therapies based on those insights and thus has major translational medicine value and implications. The number of HME patients is relatively small, but the community of their families is large. This project will thus provide a renewed sense of hope to patients and families alike that this disease will continue to be actively studied and a cure may one day be found.