# Pathogenic Mechanisms in Hereditary Multiple Exostoses Syndrome

> **NIH NIH R01** · CHILDREN'S HOSP OF PHILADELPHIA · 2021 · $358,512

## Abstract

Hereditary Multiple Exostoses (HME) is a rare autosomal dominant disorder that affects about 1 in 50,000
children worldwide. HME is characterized by cartilaginous tumors called exostoses that form in perichondrial
cells along the growth plates and protrude into surrounding tissues. The exostoses can thus cause skeletal
deformities, compression of nerves and blood vessels, chronic pain, and become malignant in about 5% of the
patients. Current therapies are limited, and patients struggle with pain and limited mobility and undergo
multiple surgeries through life. Most HME patients bear a heterozygous mutation in EXT1 or EXT2 that are
responsible for heparan sulfate (HS) synthesis, thus causing a partial systemic HS deficiency. The HS chains -
and the proteoglycans of which they are part- regulate and distinctly modulate many processes. Notably, they
interact with and stimulate signaling by fibroblast growth factors, but interact and inhibit signaling by bone
morphogenetic proteins. FGFs and BMPs generally exert anti- and pro-chondrogenic roles, respectively.
However, it was unclear whether HS partial decrease is sufficient for exostosis formation, whether HS loss
reverses those signaling activities –thus decreasing FGF and increasing BMP signaling-, and whether such
changes induce exostosis formation. In the previous funding period, we made significant progress. We created
Ext1+/-, double Ext1+/-;Ext2+/- and conditional Ext1-null mice. While single het mice were largely normal,
double hets and conditional-null mice (both producing far less HS) displayed multiple exostoses and mimicked
human HME. Exostosis development was preceded by local decreased levels of FGF signal transducers
pMEK/pERK and increased levels of BMP signaling mediators pSmad1/5/8. In vitro studies reinforced these
findings. Counter-intuitively, the HS deficiency also stimulated endogenous heparanase expression, likely
enhancing chondrogenesis even further. Indeed, treatment with recombinant heparanase stimulated BMP
signaling and chondrogenesis, while the heparanase inhibitor Roneparstat blocked both. Our central
hypothesis is that exostosis formation is caused by: (i) a steep local deficiency in HS; (ii) decreased FGF
signaling and increased BMP signaling; and (iii) a boost in chondrogenic potentials in mutant cells along the
chondro-perichondrial border. We posit also that exostosis formation is preventable by drug treatment. The
project will continue to provide fundamentally new insights into the cellular and molecular mechanisms of
exostosis formation and by extension on the normal functioning of these mechanisms in normal perichondrial
and growth plate cells. It will also test possible therapies based on those insights and thus has strong basic
research value and translational medicine implications. The number of HME patients is relatively small, but
the community of their families is large. This project will thus provide a renewed sense of hope to patients and
families alik...

## Key facts

- **NIH application ID:** 10076547
- **Project number:** 5R01AR061758-10
- **Recipient organization:** CHILDREN'S HOSP OF PHILADELPHIA
- **Principal Investigator:** Maurizio Pacifici
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $358,512
- **Award type:** 5
- **Project period:** 2011-07-01 → 2022-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10076547

## Citation

> US National Institutes of Health, RePORTER application 10076547, Pathogenic Mechanisms in Hereditary Multiple Exostoses Syndrome (5R01AR061758-10). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10076547. Licensed CC0.

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