# Pathogenic Mechanisms in Hereditary Multiple Exostoses Syndrome

> **NIH NIH R01** · CHILDREN'S HOSP OF PHILADELPHIA · 2024 · $375,584

## Abstract

Hereditary Multiple Exostoses (HME) is a rare autosomal dominant disorder that affects thousands of children
worldwide. HME is characterized by cartilaginous-bony tumors called osteochondromas that form within
perichondrium along growth plates and protrude into and collide with surrounding tissues. The tumors can
thus cause skeletal deformities, compression of nerves and blood vessels and chronic pain, and become
malignant in about 2-3% of 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 signaling proteins including bone morphogenetic proteins (BMPs)
and hedgehog family members and most often restrict and delimit protein distribution, availability and
activity. However, it is not clear whether and which of these mechanisms may be deranged in HME and how it
could lead to tumor formation. In the previous funding period, we found that conditional ablation of Ext1
caused an increase in pro-chondrogenic BMP signaling in perichondrium and a concurrent decrease in anti-
chondrogenic pERK1/2 and Noggin, deranging normal homeostatic mechanisms that normally maintain the
perichondrium phenotype. In preliminary studies, we have aimed to clarify how the osteochondromas acquire
a growth plate-like organization, are able to grow unidirectionally against surrounding tissues and thus create
damage and havoc. We have obtained evidence for the establishment of an IHH-PTHrP axis driving tumor
outgrowth. Our central hypotheses is that osteochondroma development and outgrowth are driven by: (i) a
steep local deficiency in HS; (ii) increased BMP signaling; and (iii) establishment of a neo IHH-PTHrP loop. As
a result, we posit that osteochondroma development and growth are amenable to drug treatments directed
against components of those regulatory circuits. We will use genetic, biochemical and cellular approaches and
transgenic mouse models that closely mimic human disease progression and burden. The project will continue
to provide fundamentally new insights into cellular and molecular mechanisms of tumor formation as well as
normal functioning of those mechanisms in standard perichondrial and growth plate cells. It will also test
possible therapies based on those insights and thus has major translational medicine value and 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 alike that this disease will continue to be actively
studied and a cure may one day be found.

## Key facts

- **NIH application ID:** 10816473
- **Project number:** 5R01AR061758-13
- **Recipient organization:** CHILDREN'S HOSP OF PHILADELPHIA
- **Principal Investigator:** Maurizio Pacifici
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $375,584
- **Award type:** 5
- **Project period:** 2011-07-01 → 2027-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10816473

## Citation

> US National Institutes of Health, RePORTER application 10816473, Pathogenic Mechanisms in Hereditary Multiple Exostoses Syndrome (5R01AR061758-13). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10816473. Licensed CC0.

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