Multiple hereditary exostoses (MHE) is an autosomal dominant bone disorder caused by heterozygous mutations of EXT1 or EXT2, which jointly encode a glycosyltransferase essential for heparan sulfate biosynthesis. MHE is the most common genetic bone dysplasia and thought to affect several thousand Americans. During the current funding cycle, we elucidated a long- standing puzzle concerning the genetic mechanism of MHE. Specifically, we demonstrated that loss of heterozygosity modeled via stochastic conditional knockout results in the recapitulation of essentially all human MHE phenotypes. Based on this achievement and novel questions revealed by these studies, we will explore further this debilitating disease, with goals of understanding its complete pathogenic mechanism and identifying novel biomarkers and potential therapeutic targets. We propose the following aims. 1. Determine the origin of osteochondroma: While our studies elucidated the genetic mechanisms of osteochondromatogenesis, the cellular mechanisms by which a small number of Ext1 null cells develop into osteochondromas remains almost entirely elusive. One of the critical issues is whether osteochondromas are originated either from growth plate chondrocytes or from the perichondrium. We will perform perichondrium-specific Ext1 knockout and the analysis of perichondrial progenitor cells lacking Ext1 to address this issue. 2. Determine the affected signaling pathway that is critical for osteochondromatogenesis: Another critical issue is what is the defective signaling pathway directly responsible for osteochondromatogenesis. Based on strong preliminary evidence, we will focus on the BMP pathway and determine whether aberrant BMP signaling is the main molecular culprit underlying the disease. 3. Genome-wide analysis of osteochondroma transcriptome: We will perform a state-of-the-art bioinformatics study to determine transcriptomic changes that define osteochondroma. By applying the weighted gene coexpression network analysis on RNA microarray data sets, we will identify molecular signatures that distinguish osteochondroma from normal chondrocytes and potential genetic biomarkers to predict the future severity and recurrence of osteochondroma in MHE patients.

Public Health Relevance

Multiple hereditary exostoses (MHE) is a highly debilitating genetic bone disorder affecting several thousands of people in the US, which is caused by genetic defects in heparan sulfate synthesis. This research seeks to elucidate the pathogenic mechanisms of MHE and to identify molecular signatures that correlate with the severity of the disease. This research is highly relevant to public health because it seeks to identify biomarkers and potential therapeutic targets for MHE. Additionally, this research can provide novel insight into other bone diseases, such as solitary osteochondroma, fibrodysplasia ossificans progressiva (FOP), and osteoporosis, in which heparan sulfate is also thought to play a role in their pathogenesis.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Project (R01)
Project #
2R01AR055670-06A1
Application #
8698105
Study Section
Skeletal Biology Development and Disease Study Section (SBDD)
Program Officer
Tyree, Bernadette
Project Start
2007-12-01
Project End
2019-03-31
Budget Start
2014-04-04
Budget End
2015-03-31
Support Year
6
Fiscal Year
2014
Total Cost
$429,000
Indirect Cost
$209,000
Name
Sanford-Burnham Medical Research Institute
Department
Type
DUNS #
020520466
City
La Jolla
State
CA
Country
United States
Zip Code
92037
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Huegel, Julianne; Mundy, Christina; Sgariglia, Federica et al. (2013) Perichondrium phenotype and border function are regulated by Ext1 and heparan sulfate in developing long bones: a mechanism likely deranged in Hereditary Multiple Exostoses. Dev Biol 377:100-12
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