Analysis of exostoses in mice indicate signaling defects in chondrocytes give rise to ectopic growth.

Abstract 2005 MHE Conference

Beverly M. Zak†, Manuela Schuksz†, Dominique Stickens‡, Dan Wells*, & Jeffrey D. Esko†
† Department of Cellular and Molecular Medicine, University of California, San Diego,
9500 Gilman Drive,  La Jolla, CA, 92093-0687;   
‡ Department of Anatomy, University of California, San Francisco, 513 Parnassus Ave.,  
San Francisco, CA 94143
* Department of Biology and Biochemistry, University of Houston, Houston, TX  77204

Hereditary Multiple Exostoses (HME) is an autosomal dominant disease characterized by osteochondromas on the ends of bones
that form by endochondral ossification.  The disease has been linked to mutations in EXT1 and EXT2, which encode subunits of
the heparan sulfate copolymerase.  

To understand how a change in heparan sulfate biosynthesis might result in exostoses, null alleles of each gene have been
created in mice. Homozygous null embryos arrest development at gastrulation, but heterozygous embryos appear normal,
develop to maturity, and reproduce.  

They also exhibit occasional exostoses on the ribs and more rarely on other endochondral bones.  EXT1 and EXT2
heterozygotes form exostoses at approximately the same frequency (14/101 and 20/120, respectively), whereas compound
heterozygotes (EXT1+/-EXT2+/-) develop exostoses more frequently (60/165) consistent with the two genes acting through a
common pathway.  

The exostoses arising in single and compound heterozygotes are indistinguishable by a number of criteria.

Immunohistochemical and biochemical analyses revealed reduction of heparan sulfate in affected growth plates and in cultured
chondrocytes, leading to shorter heparan sulfate chains.  This in turn results in growth factor signaling defects in isolated
chondrocytes.  Exostoses appear to arise in perichondrial chondrocytes based on the histology of affected ribs and the
appearance of exostoses in mice harboring a chondrocyte-specific inactivation of EXT1.  

Thus, we propose that signaling defects specifically in chondrocytes give rise to ectopic growth.  
The actual signaling pathway altered in heterozygous EXT animals will be discussed along with other phenotypes of mice altered
in heparan sulfate biosynthesis.
Dr. Esko serves on the Scientific and Medical Advisory Board of the MHE Research Foundation and was past
president of the
Society of Glycobiology
Research authored by Dr. Esko
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List of Publications via PubMed
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Jeffrey D. Esko Ph.D. research
The Society for Glycobiology presented the 2007 Karl Meyer award to Dr. Esko during there annual conference.
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2009 Conference abstract
Do Mutations in EXT1 or EXT2 Affect Non-Skeletal Tissues?

Jeffrey D. Esko
Department of Cellular and Molecular Medicine, University of California-San Diego, La Jolla, CA 92093.


Heparan sulfate proteoglycans reside on the plasma membrane of virtually all animal cells studied to date and represent major
components of extracellular matrices. Studies of model organisms and human diseases demonstrate their importance in
development and normal physiology. A recurrent theme is the electrostatic interaction of the heparan sulfate chains with protein
ligands, which affects metabolism, transport, information transfer, support and regulation in all organ systems studied to date
(Bishop et al., 2007). The importance of these interactions is exemplified by phenotypic studies of mice and humans bearing
mutations in the core proteins or the biosynthetic enzymes responsible for assembly of the heparan sulfate chains. Most of
these conclusions have been based on homozygous mutations, which lead to profound alterations in heparan sulfate structure.
Hereditary Multiple Exostoses (HME) is caused by autosomal dominant mutations in genes that code for subunits of the heparan
sulfate copolymerase, EXT1 and EXT2. In most tissues studied to date, heterozygous mutations in either gene results in
truncated chains. However, the phenotype associated with these mutations appears to be restricted to the cartilage growth
plate, which is somewhat surprising given the biological importance of heparan sulfate in other tissues. Recent studies of
heparan sulfate in several systems will be discussed, including studies of vascular permeability, lipoprotein metabolism mediated
by vascular and hepatic proteoglycans, and microbial infection. Further phenotypic analyses of patients and model organisms are
needed to determine if truncation of the chains caused by etiological mutations in EXT1 or EXT2 result in changes in physiology
and metabolism.
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