# Pathogenesis and Treatment of Bone Disease in the Mucopolysaccharidoses

> **NIH NIH R01** · UNIVERSITY OF PENNSYLVANIA · 2020 · $150,325

## Abstract

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 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.

## Key facts

- **NIH application ID:** 10136159
- **Project number:** 3R01AR071975-04S1
- **Recipient organization:** UNIVERSITY OF PENNSYLVANIA
- **Principal Investigator:** Lachlan James Smith
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $150,325
- **Award type:** 3
- **Project period:** 2017-08-01 → 2022-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10136159

## Citation

> US National Institutes of Health, RePORTER application 10136159, Pathogenesis and Treatment of Bone Disease in the Mucopolysaccharidoses (3R01AR071975-04S1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10136159. Licensed CC0.

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