# Development of Pharmacological Treatment of Osteochondromas

> **NIH NIH R01** · UNIVERSITY OF MARYLAND BALTIMORE · 2020 · $305,910

## Abstract

Abstract
 Osteochondromas are the most common skeletal tumors during childhood or adolescence. The tumors
grow over time and cause skeletal deformities, nerve compression, pain and other health problems.
Osteochondromas are primarily treated surgically and thereby treatment for multiple osteochondromas may
require repetitive surgery. Osteochondromas located at a high-risk site for surgery may be managed non-
surgically, however, this increases the potential for progression to malignant chondrosarcomas. The final goal
of this project is to develop non-surgical therapies that would stop osteochondroma formation and growth in an
effective manner. Multiple osteochondromas can be caused by mutations in the heparan sulfate synthases
EXT1 or EXT2. Research from our lab and other groups have indicated that reduction in heparan sulfate
induce alterations of multiple signaling pathways, leading to osteochondromas. Our long-term studies on
nuclear retinoic acid receptor gamma (RARγ) reveal that (1) pharmacologic activation of RARγ strongly inhibits
ectopic cartilage formation; (2) RARγ is expressed in cartilage elements in mouse and human
osteochondromas; and (3) RARγ agonists inhibited ectopic cartilage formation and induced involution of
existing cartilaginous tumor masses in the osteochondroma mouse model. We hypothesize that RARγ could
be a novel pharmaco-therapeutic target for osteochondromas by an anti-chondrogenic action and pro-
hypertrophic action. The cell origin of osteochondromas remains to be clarified. We have recently discovered a
novel cell population of chondroprogenitors contributing to appositional width growth of growth plate. These
cells are Wnt-responsive skeletal progenitors and reside in growth plate and the neighboring perichondrium.
We hypothesize that aberrant regulation of these progenitors induce osteochondromas and RARγ signaling
ameliorates their altered nature. To test these hypotheses, we propose three aims: Aim 1, To establish
therapeutic efficacy of RARγ agonists and examine their molecular actions in the mouse osteochondroma
model; Aim 2, To determine the cells that contribute to osteochondroma formation and growth and their
response to RARγ signaling; and Aim3, To investigate the actions of RARγ agonists on human
osteochondroma cells. The study involves diverse experimental procedures encompassing drug treatment with
mice, histological and molecular biological assessments of the mouse disease models, high throughput gene
expression analysis and study on human tumor cells. The Project will test innovative ideas on the
pathogenesis of osteochondroma and equally innovative ideas on how to combat them therapeutically.

## Key facts

- **NIH application ID:** 9858255
- **Project number:** 5R01AR073181-02
- **Recipient organization:** UNIVERSITY OF MARYLAND BALTIMORE
- **Principal Investigator:** MOTOMI ENOMOTO-IWAMOTO
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $305,910
- **Award type:** 5
- **Project period:** 2019-02-01 → 2024-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9858255

## Citation

> US National Institutes of Health, RePORTER application 9858255, Development of Pharmacological Treatment of Osteochondromas (5R01AR073181-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9858255. Licensed CC0.

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