Hereditary Multiple Exostosis Syndrome: Pathogenesis and Treatment

描述(申请人提供)：本申请涉及挑战领域(15)“转化科学”和挑战主题15-OD(ORDR)-101“罕见疾病预防、早期发现和治疗试点项目”。遗传性多发性骨瘤综合征(HME)是一种罕见的常染色体显性遗传性疾病，大约每50,000名儿童和青少年中就有1名患病。HME的特征是软骨覆盖的肿瘤与骨骼元素生长板相邻生长，并突出并侵袭周围的组织和器官。因此，骨外骨质可导致生长迟缓、神经和肌腱受压、骨骼畸形和早发性骨关节炎，并在约5%的患者中变为恶性。目前的治疗方法是姑息治疗，患者一生中都在与疼痛、活动受限和疲劳作斗争，并接受多次手术。这种情况尤其令人沮丧，因为导致70%以上HME病例的基因已经知道好几年了。这些基因是EXT1和EXT2，它们编码高尔基体相关的糖基转移酶，负责合成硫酸乙酰肝素(HS)。这些患者是EXT1或EXT2功能丧失突变的杂合子，他们的细胞产生较低的HS量。HS链通过不同的机制调节关键的生理过程，最显著的是通过限制信号因子在组织中的地形分布，但目前尚不清楚这种信号限制机制中的缺陷是否会抑制HME。在使用表达低HS-PGs(Perlecan和Syndecans)的小鼠突变体的初步研究中，我们发现一个关键的生长板信号因子--印度刺猬--广泛且异常地分布在生长板和邻近的软骨膜中，随后发生了外生骨软骨瘤的形成。在其他的初步研究中，我们创造了Ext突变小鼠，它们在长骨和肋骨中形成外突，这是人类HME的第一个真正的模型。利用这些新的发现和创新的动物模型，我们建议识别和测试HME的发病机制。我们的中心假设是，HS产量不足会导致成软骨因子(最明显的是印度刺猬)从上生长板区域渗漏到邻近的软骨膜，改变与软骨膜相关的前体细胞的发育程序，并刺激异位软骨生成和外生骨形成(目标1)。然后，我们将测试是否可以通过药物干预Hedgehog信号和相关的转录软骨生成开关来防止外生骨软骨瘤的形成(目标2)。这项挑战拨款将通过利用我们对这种被忽视、痛苦和虚弱的人类疾病的新型小鼠模型，启动对HME发病机制的机制研究，将确定干预的分子靶点，并将测试一种特定的治疗策略，以防止骨软骨瘤的形成。HME患者数量不多，但他们的家庭社区很大。因此，该项目将给患者和家属带来新的希望，即这种被忽视的疾病将得到积极研究，有朝一日可能会找到治疗方法。遗传性多发性外生性骨瘤综合征(HME)是一种严重的疾病，每50,000名儿童和青少年中就有一人患病，导致生长迟缓、持续性疼痛、活动受限和疲劳，并与骨恶性肿瘤有关。目前还没有治愈或有效的治疗方法，因此本项目旨在确定发病机制，并测试一种特定的治疗方法，以防止这种疾病典型的肿瘤样骨(外生骨软骨瘤)的形成。

DESCRIPTION (provided by applicant): This application addresses the Challenge Area (15) "Translational Science" and the Challenge Topic 15- OD(ORDR)-101 "Pilot Projects for Prevention, Early Detection and Treatment of Rare Diseases". Hereditary Multiple Exostosis Syndrome (HME) is a rare autosomal dominant disorder that affects about 1 in 50,000 children and adolescents. HME is characterized by cartilage-capped tumors that grow adjacent to the growth plates of skeletal elements and protrude into, and impinge onto, surrounding tissues and organs. The exostoses can thus cause growth retardation, compression of nerves and tendons, skeletal deformities and early onset osteoarthritis, and become malignant in about 5% of patients. Current therapies are palliative, and patients struggle with pain, limited mobility and fatigue and undergo multiple surgeries throughout their lives. This situation is particularly frustrating because the genes responsible for over 70% of HME cases have been known for several years. The genes are EXT1 and EXT2 that encode Golgi-associated glycosyltransferases responsible for heparan sulfate (HS) synthesis. The patients are heterozygous for EXT1 or EXT2 loss-of-function mutations and their cells produce lower HS amounts. HS chains regulate key physiologic processes and do so by various mechanisms and most notably by restricting the topographical distribution of signaling factors within tissues, but it is not known whether defects in such signal-restriction mechanisms subtend HME. In Preliminary Studies using mouse mutants expressing low HS-PGs (perlecan and syndecans), we found that a key growth plate signaling factor -Indian hedgehog- was widely and abnormally distributed within growth plate and adjacent perichondrium, and this was followed by exostosis formation. In additional Preliminary Studies, we created Ext mutant mice that develop exostoses in long bones and ribs and that are the first genuine model of human HME. Using these novel findings and innovative animal models, we propose to identify and test mechanisms of HME pathogenesis. Our central hypothesis is that deficiency in HS production causes leakage of chondrogenic factors (most notably Indian hedgehog) from upper growth plate zones into adjacent perichondrium, altering the developmental program of perichondrium-associated progenitor cells and inciting ectopic chondrogenesis and exostosis formation (Aim 1). We will then test whether exostosis formation can be prevented by pharmacologic interference with hedgehog signaling and associated transcriptional chondrogenic switches (Aim 2). This Challenge Grant will jump-start mechanistic research on HME pathogenesis by exploiting our novel mouse models of this neglected, painful and debilitating human disorder, will identify molecular targets of intervention, and will test a specific therapeutic strategy to prevent exostosis formation. The number of HME patients is 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 neglected disease will actively be studied and a cure may one day be found. Hereditary Multiple Exostosis Syndrome (HME) is a serious disease that affects about 1 in 50,000 children and adolescents, causes growth retardation, continuous pain, limited mobility and fatigue, and are associated with bone malignant tumors. There are no cures or effective treatments at the moment, and this project thus aims to identify the mechanisms of pathogenesis and test a specific therapeutic treatment to prevent formation of tumor-like bone (exostosis) typical of this disease.