Pathogenesis and Treatment of Bone Disease in the Mucopolysaccharidoses

粘多糖症骨病的发病机制及治疗

• 批准号: 10171788
• 负责人: Lachlan James Smith
• 金额: $ 34.42万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-08-01 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10171788
• 关键词: Affinity; Age; Animal Model; Beta-glucuronidase; Binding; Biological Assay; Birth; Bone Diseases; Bypass; Canis familiaris; Cartilage; Cell physiology; Cells; Chondrocytes; Chondroitin Sulfates; Clinical; Deformity; Dermatan Sulfate; Development; Disease; Disease Progression; Distributional Activity; Dose; Enzymes; Exhibits; Failure; Functional disorder; Glycosaminoglycans; Growth; Growth Factor; Heparitin Sulfate; Human; Hypertrophy; Impairment; Joints; Laboratories; Lesion; Ligands; Link; Lithium; Lithium Carbonate; Modeling; Molecular; Mucopolysaccharidoses; Mucopolysaccharidosis VII; Osteogenesis; Paralysed; Pathogenesis; Pathologic; Pathway interactions; Patients; Phenotype; Physiologic Ossification; Role; Signal Pathway; Signal Transduction; Stress; Therapeutic; Tissues; Vertebral Bone; Work; beta catenin; bone; cartilaginous; chronic pain; clinically relevant; effective therapy; endoplasmic reticulum stress; enzyme replacement therapy; extracellular; family genetics; improved; in vivo; long bone; osteoblast differentiation; osteogenic; postnatal; postnatal development; skeletal; skeletal abnormality; skeletal disorder; spatial relationship; spinal cord compression; spine bone structure; therapeutic target; transcriptome sequencing; Affinity; Age; Animal Model; Beta-glucuronidase; Binding; Biological Assay; Birth; Bone Diseases; Bypass; Canis familiaris; Cartilage; Cell physiology; Cells; Chondrocytes; Chondroitin Sulfates; Clinical; Deformity; Dermatan Sulfate; Development; Disease; Disease Progression; Distributional Activity; Dose; Enzymes; Exhibits; Failure; Functional disorder; Glycosaminoglycans; Growth; Growth Factor; Heparitin Sulfate; Human; Hypertrophy; Impairment; Joints; Laboratories; Lesion; Ligands; Link; Lithium; Lithium Carbonate; Modeling; Molecular; Mucopolysaccharidoses; Mucopolysaccharidosis VII; Osteogenesis; Paralysed; Pathogenesis; Pathologic; Pathway interactions; Patients; Phenotype; Physiologic Ossification; Role; Signal Pathway; Signal Transduction; Stress; Therapeutic; Tissues; Vertebral Bone; Work; beta catenin; bone; cartilaginous; chronic pain; clinically relevant; effective therapy; endoplasmic reticulum stress; enzyme replacement therapy; extracellular; family genetics; improved; in vivo; long bone; osteoblast differentiation; osteogenic; postnatal; postnatal development; skeletal; skeletal abnormality; skeletal disorder; spatial relationship; spinal cord compression; spine bone structure; therapeutic target; transcriptome sequencing

Abstract The mucopolysaccharidoses (MPS) are a family of genetic, lysosomal storage disorders characterized by deficiencies in enzymes that degrade glycosaminoglycans (GAGs). Patients with MPS suffer from crippling skeletal abnormalities that are unresponsive to current treatments. MPS VII presents with a particularly severe skeletal phenotype, where patients exhibit progressive kyphoscoliotic deformity and spinal cord compression resulting in chronic pain and paralysis. MPS VII is caused by deficient beta-glucuronidase activity, leading to accumulation of multiple GAG types. The molecular mechanisms linking this GAG accumulation to cellular dysfunction and skeletal disease are poorly understood, impeding development of effective therapies. Our laboratory uses a clinically-relevant, naturally-occurring canine model of MPS VII that closely mimics the progression of skeletal disease that occurs in human patients. In previous work we demonstrated that MPS VII dogs have cartilaginous lesions in the vertebrae that compromise the stability of the intervertebral joint. These lesions are caused by failed conversion of cartilage to bone during postnatal growth. In preliminary studies, we have identified the precise developmental window when abnormal ossification first manifests in MPS VII dogs and that this can be traced to a failure of resident chondrocytes to progress through hypertrophic maturation. We have also shown that there is abnormal GAG accumulation in MPS VII epiphyseal cartilage from an early age, and, using whole transcriptome sequencing, that there is dysregulation of the Wnt/β-catenin signaling pathway at this crucial juncture in the disease progression. Wnt growth factors are critical regulators of chondrocyte differentiation, and GAGs are known to be important regulators of Wnt distribution and activity, suggesting a link between GAG accumulation and dysregulation of this pathway. The objectives of this proposal are to investigate mechanisms of failed bone formation in MPS VII and establish improved treatment paradigms using a clinically-relevant canine model. Our central hypothesis is that abnormal accumulation of GAGs in MPS VII epiphyseal cartilage disrupts the signaling pathways necessary to initiate and sustain chondrocyte hypertrophic differentiation. Further, we hypothesize that to effectively treat bone disease in MPS VII, it will be necessary to both normalize GAG turnover and activate requisite osteogenic signaling pathways in epiphyseal cartilage. In Aim 1 we will define temporal and spatial relationships between GAG accumulation and epiphyseal chondrocyte differentiation potential at key stages of bone disease progression in MPS VII dogs, from birth to skeletal maturity. In Aim 2 we will establish the critical role of Wnt/β-catenin signaling dysregulation in delayed epiphyseal bone formation in MPS VII dogs. In Aim 3 we will establish if therapeutic targeting of Wnt/β-catenin signaling, alone and in combination with enzyme replacement therapy, can enhance bone formation in MPS VII dogs.

抽象的 粘多糖糖（MPS）是一个以遗传性，溶酶体储存障碍为特征的家族 酶降解糖胺聚糖（插科打）的酶缺陷。国会议员患者遭受残酷的痛苦 对当前治疗无反应的骨骼异常。国会议员VII呈现特别严重 骨骼表型，患者表现出进行性脑震荡的畸形和脊髓压缩 导致慢性疼痛和麻痹。 MPS VII是由不足的β-葡萄糖醛酸酶活性引起的，导致 多种插科打式类型的积累。将这种GAG积累与细胞联系起来的分子机制 功能障碍和骨骼疾病知之甚少，阻碍了有效疗法的发展。我们的 实验室使用与MPS VII的临床相关的，自然存在的犬模型，该模型紧密模仿 人类患者发生的骨骼疾病的进展。在以前的工作中，我们证明了国会议员VII 狗在椎骨中有软骨病变，会损害椎骨关节的稳定性。这些 病变是由于在产后生长过程中软骨转化为骨骼的失败引起的。在初步研究中，我们 当骨化异常在MPS VII狗中首次表现出来时，已经确定了精确的发育窗口 并且可以追溯到居民软骨细胞通过肥厚性成熟而发生的失败。 我们还表明，MPS VII epiphyseal软骨中有异常的GAG积累 年龄，并使用整个转录组测序，即Wnt/β-catenin信号传导失调 疾病进展的关键时刻的途径。 Wnt增长因素是关键的调节因素 软骨细胞分化和插科打s已知是Wnt分布和活性的重要调节剂， 表明该途径的GAG积累与失调之间有联系。目标的目标 提案是研究MPS VII中骨形成失败的机制，并建立了改善 使用与临床相关的犬模型处理范例。我们的中心假设是异常 MPS VII epiphyseal软骨中GAG的积累破坏了所需的信号通路 引发和维持软骨细胞肥厚性分化。此外，我们假设 有效治疗MPS VII中的骨病 激活必要的成骨信号传导途径。在AIM 1中，我们将定义临时性 与插科打g的积累与外周性软骨细胞分化潜力之间的空间关系 从出生到骨骼成熟的MPS VII犬骨骼疾病进展的关键阶段。在目标2中，我们将 建立Wnt/β-catenin信号传导失调在MPS中延迟的附着骨形成中的关键作用 vii狗。在AIM 3中，我们将单独和组合确定Wnt/β-catenin信号传导的治疗靶向是否 通过酶替代疗法，可以增强MPS VII犬的骨形成。