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Pathogenesis and Treatment of Bone Disease in the Mucopolysaccharidoses

粘多糖症骨病的发病机制及治疗

基本信息

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
项目类别：
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

项目摘要

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.

摘要