# Pathogenesis and Treatment of Bone Disease in the Mucopolysaccharidoses

> **NIH NIH R01** · UNIVERSITY OF PENNSYLVANIA · 2020 · $354,817

## 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 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 r...

## Key facts

- **NIH application ID:** 9932910
- **Project number:** 5R01AR071975-04
- **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:** $354,817
- **Award type:** 5
- **Project period:** 2017-08-01 → 2022-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9932910

## Citation

> US National Institutes of Health, RePORTER application 9932910, Pathogenesis and Treatment of Bone Disease in the Mucopolysaccharidoses (5R01AR071975-04). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/9932910. Licensed CC0.

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