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: 9020928
• 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 2018-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9020928
• 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 Receptors; Health; 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; Treatment Factor; Vertebral Bone; Vertebral column; Work; age related; aged; airway obstruction; body system; bone; differential expression; enzyme deficiency; extracellular; mRNA Expression; mortality; new therapeutic target; polysulfated glycosaminoglycan; postnatal; prevent; protein expression; regional difference; response; small molecule; spinal cord compression; spine bone structure; therapeutic target; transcription factor; vertebra body; 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 Receptors; Health; 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; Treatment Factor; Vertebral Bone; Vertebral column; Work; age related; aged; airway obstruction; body system; bone; differential expression; enzyme deficiency; extracellular; mRNA Expression; mortality; new therapeutic target; polysulfated glycosaminoglycan; postnatal; prevent; protein expression; regional difference; response; small molecule; spinal cord compression; spine bone structure; therapeutic target; transcription factor; vertebra body

DESCRIPTION (provided by applicant): 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 cartilae 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.

描述（由申请人提供）：粘二糖（MPS）是溶酶体储存障碍，其特征在于降解糖胺聚糖（GAG）的酶中的缺陷。 MPS VII的特征是不足的β-葡萄糖醛酸酶活性，导致系统性降解的软骨素，乙par和硫酸皮肤硫酸盐的系统积累。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-Scoliotic畸形。目前没有治疗方法，即临床或实验性，它们在MPS VII中纠正了脊柱疾病。我们已经表明，MPS VII犬在椎体中具有较大的软骨病变，这些病变损害了椎骨的生物力学稳定性。这些病变是由于在产后发育过程中骨软骨转化为骨骼失败的结果。导致MPS VII内软骨骨化失败的基本分子机制尚不清楚。在正常的椎骨形成期间，软骨序列形成了随后的骨化模板。填充这些基础的软骨细胞经历了不同的分化阶段，受信号通路的高度策划模式调节。印度刺猬（IHH）是软骨细胞分化的关键调节剂。插科打术在内侧软骨骨化过程中发挥关键作用，以调节IHH的稳定性，分布和结合。在试点工作中，我们已经表明，与产后发育早期相比，MPS VII犬的骨eiHH途径分子的表达发生了变化。我们的总体假设是，MPS VII中异常的插入式积累通过干扰IHH的合成，稳定性，分布和结合来破坏软骨细胞的增殖和分化，从而防止了正常的软骨与骨转化。在AIM 1中，我们将研究开发MPS VII椎骨的区域特异性和依赖性细胞内和细胞外CAG积累模式，并确定这些GAG积累模式如何对应于软骨细胞的不同阶段。在AIM 2中，我们将确定在正常和MPS VII椎骨之间的IHH和相关调节剂的表达和分布和相关调节剂中的表达和分布差异。在AIM 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挽救这些细胞的健康表型，并评估小分子IHH途径激动剂的治疗潜力。这项工作的长期目标是确定MPS VII的新治疗靶标，对于MPS疾病家族的其他11个酶缺陷以及其他涉及异常堵嘴合成或失误的遗传性肌肉骨骼疾病。