Mechanisms of Vertebral Bone Disease in Mucopolysaccharidosis VII

粘多糖贮积症椎骨疾病的机制七

• 批准号: 8702431
• 负责人: Lachlan James Smith
• 金额: $ 8万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-04-01 至 2017-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8702431
• 关键词: Age; Agonist; Beta-glucuronidase; Binding; Biochemical; Biological Assay; Biomechanics; Bone Diseases; Canis familiaris; Cartilage; Cells; Chondrocytes; Chondroitin Sulfates; Clinical Treatment; Deformity; Dermatan Sulfate; Development; Differentiation Antigens; Disease; Enzymes; Epiphysial cartilage; Erinaceidae; Extracellular Matrix; Failure; Family; Genes; Glycosaminoglycans; Goals; Growth; Growth Factor; Growth Factor Receptors; Heparitin Sulfate; Hereditary Disease; Human; Immunoblotting; Immunohistochemistry; Intervertebral disc structure; Joints; Lead; Length; Lesion; Modeling; Molecular; Mucopolysaccharidoses; Mucopolysaccharidosis I S; Mucopolysaccharidosis VII; Musculoskeletal; Musculoskeletal Diseases; Neurologic; Osteogenesis; Other Genetics; Pathway interactions; Patients; Pattern; Phenotype; Role; Signal Pathway; Signal Transduction; Staging; Testing; Therapeutic; Vertebral Bone; Vertebral column; Work; age related; aged; airway obstruction; body system; bone; enzyme deficiency; extracellular; human SMO protein; mRNA Expression; mortality; new therapeutic target; polysulfated glycosaminoglycan; postnatal; prevent; protein expression; public health relevance; regional difference; response; small molecule; spinal cord compression; spine bone structure; therapeutic target; transcription factor; vertebra body

Summary The mucopolysaccharidoses (MPS) are lysosomal storage disorders characterized by deficiencies in enzymes that degrade glycosaminoglycans (GAG). MPS VII is characterized by deficient beta-glucuronidase activity, leading to systemic accumulation of incompletely degraded chondroitin, heparan and dermatan sulfate GAGs. While disease is manifested in multiple organ systems, spine disease is particularly severe and includes morphological abnormalities in the intervertebral discs and vertebral bones, leading to spinal cord compression and kypho-scoliotic deformity. Currently there are no treatments, clinical or experimental, which correct spine disease in MPS VII. We have shown that MPS VII dogs have large, cartilaginous lesions in the vertebral bodies that compromise biomechanical stability of the intervertebral joint. These lesions are the result of failed conversion of cartilage to bone during postnatal development. The underlying molecular mechanisms that lead to this failure of endochondral ossification in MPS VII are unknown. During normal vertebral bone formation, cartilaginous rudiments form the template for subsequent ossification. The chondrocytes that populate these rudiments undergo distinct stages of differentiation, regulated by a highly orchestrated pattern of signaling pathways. Indian hedgehog (IHH) is a key regulator of chondrocyte differentiation. GAGs perform critical roles regulating the stability, distribution and binding of IHH during endochondral ossification. In pilot work we have shown that expression of key IHH pathway molecules is altered in the epiphyseal cartilage of MPS VII dogs compared to normals from early in postnatal development. Our overall hypothesis is that abnormal GAG accumulation in MPS VII disrupts chondrocyte proliferation and differentiation by interfering with the synthesis, stability, distribution and binding of IHH, preventing normal cartilage to bone conversion. In Aim 1 we will investigate region-specific and age- dependent intra- and extracellular GAG accumulation patterns in developing MPS VII vertebrae, and establish how these patterns of GAG accumulation correspond to different stages of chondrocyte maturation. In Aim 2 we will identify age-dependent differences in the expression and distribution of IHH and associated regulators of chondrocyte proliferation and hypertrophic differentiation between normal and MPS VII vertebrae. In Aim 3 we will directly evaluate the cellular response to IHH, determine if exogenous enzyme administration can rescue the healthy phenotype of these cells, and evaluate the therapeutic potential of a small molecule IHH pathway agonist. The long-term goal of this work is to identify new therapeutic targets for MPS VII, for the other 11 enzyme deficiencies of the MPS family of disorders, and for other genetic musculoskeletal disorders that involve abnormal GAG synthesis or turnover.

概括 粘二糖（MPS）是溶酶体储存障碍，其特征是酶的缺陷 这种降解糖胺聚糖（GAG）。 MPS VII的特征是不足的β-葡萄糖醛酸酶活性， 导致系统性积累不完全降解的软骨素，乙par和硫酸皮肤插孔。 虽然疾病在多个器官系统中表现出来，但脊柱疾病特别严重，包括 椎间盘和椎骨的形态异常，导致脊髓压缩 和kypho-Scolirotic畸形。目前没有临床或实验性的治疗方法 MPS VII中的疾病。我们已经表明，MPS VII犬在椎骨中有大的软骨病变 损害椎间关节生物力学稳定性的身体。这些病变是结果 在产后发育过程中软骨转化为骨骼的失败。基础分子 导致MPS VII内软骨骨化失败的机制尚不清楚。期间 正常的椎骨形成，软骨构构形成了随后的骨化模板。这 填充这些基础的软骨细胞经历了不同的分化阶段，由高度调节 信号通路的精心策划模式。印度刺猬（IHH）是软骨细胞的关键调节剂 分化。插科打术在调节IHH期间的稳定性，分布和结合的关键作用 内软骨骨化。在飞行员工作中，我们表明键IHH途径分子的表达是 与产后发育早期的正常狗相比，MPS VII犬的骨b骨软骨的发生变化。 我们的总体假设是，MPS VII中异常的插入术会破坏软骨细胞 通过干扰合成，稳定性，分布和结合来扩散和分化 IHH，防止正常的软骨转化为骨骼。在AIM 1中，我们将调查特定地区和年龄 在发展MPS VII椎骨中，依赖的细胞内和细胞外插入积累模式，并建立 这些GAG积累的模式如何对应于软骨细胞的不同阶段。在目标2中 我们将确定IHH和相关调节剂的表达和分布的年龄依赖性差异 正常和MPS VII椎骨之间的软骨细胞增殖和肥厚性分化。在目标3中 我们将直接评估对IHH的细胞反应，确定外源性酶的给药是否可以 营救这些细胞的健康表型，并评估小分子IHH的治疗潜力 途径激动剂。这项工作的长期目标是确定MPS VII的新治疗目标 MPS疾病家族的11个酶缺陷，以及其他遗传肌肉骨骼疾病 涉及异常的插科打综合或周转率。