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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.
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
Click the tab and a window will appear.
List of Publications via PubMed
(NIH National Library of Medicine)
president of the Society of Glycobiology
Research authored by Dr. Esko
Click the tab and a window will appear.
List of Publications via PubMed
(NIH National Library of Medicine)
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| Dr. Esko's research |
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| The Society for Glycobiology presented the 2007 Karl Meyer award to Dr. Esko during there annual conference. Please Click Here to read more about this award. |
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By the Health On the Net Foundation. Click here to verify.# HON Conduct 282463 and is linked on the NIH
National Library of Medicine, Directory of Health Organizations (SIS) website, as well as the link for Patient
Information on The Diseases Database a cross-referenced index of human disease, and the Intute: health & life
sciences a free online service providing access to the very best Web resources for education and research
located in the UK
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