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 signaling pathways required for chondrocyte differentiation and healthy bone formation. The objectives of this supplement award are to complement and build on the goals of the parent R01 by establishing links between abnormal GAG accumulation in MPS VII epiphyseal cartilage, dysregulated growth factor signaling and failed bone formation.
In Aim 1 we will define the nature of abnormal GAG accumulation in MPS VII epiphyseal cartilage using mass spectrometry.
In Aim 2 we will establish the differential growth facture binding potential of GAG fragments present in MPS VII epiphyseal cartilage using computational modeling. From these studies we will be able to rapidly and efficiently predict which growth factors are bound and sequestered by GAG fragments accumulating in MPS VII epiphyseal cartilage, and identify which GAG fragments, specifically are responsible for growth factor binding based on their fine structure and composition.
The mucopolysaccharidoses (MPS) are lysosomal storage disorders characterized by accumulation of poorly degraded glycosaminoglycans. MPS patients exhibit severe skeletal abnormalities, including failed bone formation during postnatal development. The objectives of this proposal supplement are to investigate mechanisms of failed bone formation in MPS VII by establishing the biological and pathological function of accumulating glycosaminoglycan fragments in epiphyseal cartilage using mass spectrometry and computational modeling.
