Jacqueline T. Hecht, Ph.D.
Scientific Staff
Houston SHC
Professor, Department of Pediatrics
University of Texas Health Science Center Houston
The EXT genes are glycosyltransferases that synthesize heparan sulfate (HS) chains necessary for the biological activity of HS
proteoglycans that regulate growth plate proliferation and differentiation. Mutations in the EXT1 and EXT2 genes cause
Hereditary Multiple Exostoses (HME), an autosomal dominant condition characterized by inappropriate bone growth at the ends
of the long bones called exostoses. Exostoses are numerous and often associated with orthopaedic complications requiring
multiple surgical interventions.
Figure 2
Figure 2. Future studies will be aimed at gaining a better understanding of normal mechanisms
of bone growth which may provide insights that will lead to nonsurgical intervention in HME.
Our studies have focused on exostosis chondrocytes to determine how mutations affect the
EXT protein levels and the chondrocyte function.
Immunocytochemistry using EXT1 and EXT2 antibodies identified significantly diminished levels
of EXT1 and EXT2 proteins.Furthermore, exostosis chondrocytes have a unique stellate
appearance with elongated inclusions in the cytoplasm composed of actin bundled by 1.5-mm
repeat crossbridges of a-actinin.
The exostosis chondrocytes produce aberrantly high levels of muscle-specific a-actin, while
b-actin levels are similar to normal chondrocytes.
Altogether, these findings suggest that mutations in the EXT genes affect the proteins
regulating chondrocyte signaling. Our studies are focused on identifying the proteoglycans
that are specifically affected by the EXT mutations.
The following model has been developed to account for the aberrant chondrocyte proliferation
and bone growth in the growth plate (Figure 2).
Figure 2. Future studies will be
aimed at gaining a better
understanding of normal
mechanisms of bone growth which
may provide insights that will lead
to nonsurgical intervention in HME.
Exostoses Development Section
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Chondrocytes (from Greek chondros cartilage + kytos cell) are the only cells found in cartilage. They produce and maintain the
cartilaginous matrix, which consists mainly of collagen and proteoglycans.
The MHE Research Foundation would like to thank Craig W. Wiesenhutter, M.D., U.C.L.A. Rheumatology Pathophysiology of
Disease Course for the use of this Chondrocyte animation.
There also other OSTEOARTHRITIS: SLIDES & ANIMATIONS and information contained on this website
http://www.cdaarthritis.com/OA/INDEX.HTM This maybe of interest to people with MHE as they can develop early on set of
osteoarthritis as a secondary complication of their MHE.
Slide: Jeffrey D Esko, Phd
Press Release 8/02/08
Regulation of Zebrafish Skeletogenesis by ext2/dackel and papst1/pinscher
Aurélie Clément1,2, Malgorzata Wiweger1,2, Sophia von der Hardt3, Melissa A. Rusch4,5, Scott B. Selleck4,5, Chi-Bin Chien6,7,
Henry H. Roehl1,2*
1 MRC Centre for Developmental and Biomedical Genetics, University of Sheffield, Sheffield, United Kingdom2 Department of
Biomedical Science, University of Sheffield, Sheffield, United Kingdom3 Abteilung Genetik, MPI für Entwicklungsbiologie,
Tuebingen, Germany4 Department of Pediatrics, University of Minnesota, Minneapolis, Minnesota, United States of America5
Department of Genetics, Cell Biology, and Development, University of Minnesota, Minneapolis, Minnesota, United States of
America6 Department of Neurobiology and Anatomy, University of Utah, Salt Lake City, Utah, United States of America7 Brain
Institute, University of Utah, Salt Lake City, Utah, United States of America
Abstract
Mutations in human Exostosin genes (EXTs) confer a disease called Hereditary Multiple Exostoses (HME) that affects 1 in
50,000 among the general population. Patients with HME have a short stature and develop osteochondromas during childhood.
Here we show that two zebrafish mutants, dackel (dak) and pinscher (pic), have cartilage defects that strongly resemble those
seen in HME patients. We have previously determined that dak encodes zebrafish Ext2. Positional cloning of pic reveals that it
encodes a sulphate transporter required for sulphation of glycans (Papst1). We show that although both dak and pic are
required during cartilage morphogenesis, they are dispensable for chondrocyte and perichondral cell differentiation. They are
also required for hypertrophic chondrocyte differentiation and osteoblast differentiation. Transplantation analysis indicates that
dak−/− cells are usually rescued by neighbouring wild-type chondrocytes. In contrast, pic−/− chondrocytes always act
autonomously and can disrupt the morphology of neighbouring wild-type cells. These findings lead to the development of a new
model to explain the aetiology of HME.
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Wings of HOPE as we REACH for the CURE to Multiple Hereditary Exostoses / Multiple Osteochondroma
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Cytoskeletal Abnormalities in Hereditary Multiple Exostosis Chondrocytes
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