Pathogenic Mechanisms in Hereditary Multiple Exostoses Syndrome

遗传性多发性外生骨疣综合征的发病机制

• 批准号: 9309201
• 负责人: Maurizio Pacifici
• 金额: $ 36.96万
• 依托单位: CHILDREN'S HOSP OF PHILADELPHIA
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-07-01 至 2021-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9309201
• 关键词: Ablation; Address; Adolescent; Adverse effects; Affect; Area; Basic Science; Benign; Blood Vessels; Bone Morphogenetic Proteins; Cartilaginous exostosis; Cell Surface Receptors; Cell surface; Cells; Child; Chondrogenesis; Chondrogenic Neoplasm; Communities; Complex; Data; Deformity; Development; Disease; Dominant-Negative Mutation; EXT1 gene; EXT2 gene; Effectiveness; Elements; Epiphysial cartilage; Exostoses; Family; Fatigue; Fibroblast Growth Factor; Funding; Genetic; Growth; Heparitin Sulfate; Hereditary Multiple Exostoses; Human; In Vitro; Intervention; Intuition; Knockout Mice; Life; Ligands; Light; MAPK14 gene; Malignant - descriptor; Mediator of activation protein; Molecular; Mus; Mutation; Nerve compression syndrome; Operative Surgical Procedures; Outcome; Output; Pain; Pathogenesis; Pathogenicity; Pathway interactions; Patients; Pattern; Pharmaceutical Preparations; Pharmacology; Pharmacotherapy; Process; Proteoglycan; Recombinants; Regimen; Role; Signal Pathway; Signal Transduction; Signaling Protein; Syndrome; Testing; Therapeutic; Tissues; Transducers; Ursidae Family; base; bone morphogenetic protein receptor type I; chronic pain; effective therapy; heparanase; inhibitor/antagonist; insight; mutant; neglect; novel; novel therapeutics; overexpression; prevent; receptor; response; skeletal; spatiotemporal; translational medicine

Hereditary Multiple Exostoses (HME) is a rare autosomal dominant disorder that affects about 1 in 50,000 children worldwide. HME is characterized by cartilaginous tumors called exostoses that form in perichondrial cells along the growth plates and protrude into surrounding tissues. The exostoses can thus cause skeletal deformities, compression of nerves and blood vessels, chronic pain, and become malignant in about 5% of the 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 and stimulate signaling by fibroblast growth factors, but interact and inhibit signaling by bone morphogenetic proteins. FGFs and BMPs generally exert anti- and pro-chondrogenic roles, respectively. However, it was unclear whether HS partial decrease is sufficient for exostosis formation, whether HS loss reverses those signaling activities –thus decreasing FGF and increasing BMP signaling-, and whether such changes induce exostosis formation. In the previous funding period, we made significant progress. We created Ext1+/-, double Ext1+/-;Ext2+/- and conditional Ext1-null mice. While single het mice were largely normal, double hets and conditional-null mice (both producing far less HS) displayed multiple exostoses and mimicked human HME. Exostosis development was preceded by local decreased levels of FGF signal transducers pMEK/pERK and increased levels of BMP signaling mediators pSmad1/5/8. In vitro studies reinforced these findings. Counter-intuitively, the HS deficiency also stimulated endogenous heparanase expression, likely enhancing chondrogenesis even further. Indeed, treatment with recombinant heparanase stimulated BMP signaling and chondrogenesis, while the heparanase inhibitor Roneparstat blocked both. Our central hypothesis is that exostosis formation is caused by: (i) a steep local deficiency in HS; (ii) decreased FGF signaling and increased BMP signaling; and (iii) a boost in chondrogenic potentials in mutant cells along the chondro-perichondrial border. We posit also that exostosis formation is preventable by drug treatment. The project will continue to provide fundamentally new insights into the cellular and molecular mechanisms of exostosis formation and by extension on the normal functioning of these mechanisms in normal perichondrial and growth plate cells. It will also test possible therapies based on those insights and thus has strong basic research value and translational medicine 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 neglected disease will continue to be actively studied and a cure may one day be found.

遗传性多发性外生骨疣（HME）是一种罕见的常染色体显性遗传病，约1/50，000 世界各地的儿童。HME的特点是软骨肿瘤称为外生骨疣，形成于软骨膜， 细胞沿着生长板并伸入周围组织。因此，外生骨疣会导致骨骼 畸形，压迫神经和血管，慢性疼痛，并在约5%的患者中变成恶性肿瘤。 患者目前的治疗方法是有限的，患者与疼痛和有限的活动能力作斗争， 做过多次手术大多数HME患者在EXT 1或EXT 2中携带杂合突变， 负责硫酸乙酰肝素（HS）的合成，从而导致部分全身性HS缺乏。HS链条- 并且它们是蛋白聚糖的一部分-调节和明显地调节许多过程。值得注意的是，他们 与成纤维细胞生长因子相互作用并刺激成纤维细胞生长因子的信号传导，但与骨生长因子相互作用并抑制骨生长因子的信号传导。 形态发生蛋白FGF和BMP通常分别发挥抗软骨形成和促软骨形成作用。 然而，尚不清楚HS部分减少是否足以形成外生骨疣，HS丢失是否足以形成外生骨疣。 逆转这些信号传导活动-从而减少FGF和增加BMP信号传导-， 变化诱导外生骨疣形成。在上一个供资期间，我们取得了重大进展。我们创建 Ext 1 +/-、双Ext 1 +/-、Ext 2 +/-和条件性Ext 1缺失小鼠。虽然单het小鼠在很大程度上是正常的， 双hets和条件无效小鼠（均产生少得多的HS）显示多个外生骨疣， 人HME。外生骨疣的发展之前，局部FGF信号转导水平下降 pMEK/pERK和增加的BMP信号传导介质pSmad 1/5/8的水平。体外研究强化了这些 调查结果。与直觉相反，HS缺乏也刺激了内源性乙酰肝素酶的表达，这可能是因为HS缺乏引起的。 进一步促进软骨形成。事实上，用重组乙酰肝素酶刺激BMP 信号传导和软骨形成，而乙酰肝素酶抑制剂Roneparstat阻断了两者。我们的中央 假设外生骨疣形成是由于：（i）HS的急剧局部缺乏;（ii）FGF减少 信号传导和增加的BMP信号传导;和（iii）增强突变细胞沿着 软骨软骨膜缘我们还认为外生骨疣的形成是可以通过药物治疗来预防的。的 该项目将继续提供从根本上新的见解的细胞和分子机制， 外生骨疣的形成，并通过扩展这些机制在正常软骨膜的正常功能， 和生长板细胞。它还将测试基于这些见解的可能疗法，因此具有强大的基础 研究价值和转化医学意义。HME患者的数量相对较少，但 他们的家庭社区很大。因此，该项目将为患者带来新的希望， 我们向所有家庭表示，将继续积极研究这种被忽视的疾病，有朝一日可能会找到治愈方法。