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Researchers Devoted To MHE

There are a handful of researchers working on treatment and prevention of MHE.  Since this is such a rare disease, there isn't much funding available for these efforts.  However, since MHE effects the body's ability to produce Heparan Sulfate; an enzyme known as a "tumor supressor", there could be many byproducts of this research benefiting many other diseases including cancer.  

Research Publications

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Below are the researchers who are involved with the MHE Research Foundation and brief description of their area of focus for MHE.

Yu Yamaguchi, Ph. D. - SBP Medical Discovery Institute in La Jolla, California

My laboratory has been studying the role of EXT1/heparan sulfate in mouse embryonic development.  We have created a conditional EXT1 knockout mouse model.  These conditional EXT1 knockout mice are being used for genetic studies to figure out how the deficiency of EXT1/heparan sulfate causes MHE.  

These conditional knockout mice, which allow knocking out EXT1 at the site and time of researchers' desire, are very useful for diverse studies on the function of EXT1/heparan sulfate.

Dr. Yamaguchi and his lab have been able to distribute these mice to more than 20 laboratories around the world (US, Europe, and Japan) to help studies by other MHE investigators. Using this model system, Dr. Yamaguchi has demonstrated that mutations of EXT1 influence not only bones but also the nervous system. Through an informal survey conducted by Sarah 
Ziegler and Dr. Yamaguchi, although frequently ignored in the clinical front, MHE patients tend to have some mental, neurological, and muscular symptoms. Such symptoms include: mild social interaction deficits (excessive shyness, adherence to routines), heightened sensitivities to sensory stimulation (sounds, touch, taste), difficulties to concentrate, sleep issues and muscle weakness(easy to get tired) and pain. Dr. Yamaguchi believes these neurological symptoms can be explained by the deficiency of heparan sulfate in nerve cells. Indeed, recent analysis of knockout mouse behavior has revealed that these mice have deficits in certain aspects of learning and the levels of fear/anxiety, as well as alterations in nerve cell wiring.

In addition, Dr. Yamaguchi has recently discovered that knockout of EXT1 in stem cells that destined to become bones and cartilage causes severe bone abnormalities. These findings have provided us with a new insight into the reason why MHE patients frequently associate a variety of symptoms in addition to exostosis /osteochondroma formation, and suggests 
potential novel MHE treatment paradigms.

Jeffrey D. Esko, Ph.D. - University of California, San Diego

Research in Dr. Esko’s laboratory focuses on the structure, biosynthesis, and function of proteoglycans. Current work includes structural studies of heparan sulfate by mass spectrometry; studies of 3-O-sulfation of heparan sulfate; application of genome-wide methods to identify novel genes involved in heparan sulfate assembly; analysis of guanidinylated glycosides that bind to proteoglycans and facilitate delivery of high molecular weight cargo into the interior of the cell; studies of proteoglycans in lipoprotein metabolism; and studies on the role of proteoglycans in inflammation. His lab has extensive experience in the isolation and characterization of glycosaminoglycans, selection and characterization of mutant cell lines altered in glycosaminoglycan metabolism, and development of genetic models altered in glycosaminoglycan metabolism in mice.

Several studies in his lab focus specifically on Hereditary Multiple Exostoses. Early on his group characterized heparan sulfate-deficient cell lines and demonstrated genetically that alteration of Ext1 affected the copolymerization of heparan sulfate in vivo and in vitro. He also mapped the glucuronosyltransferase domain in Ext1. His group characterized Ext1 and Ext2 deficient mice, and were the first group to demonstrate that the animals develop exostoses on the ribs. Subsequent studies have shown that the formation of exostoses exhibits gene dosage effects and that the exostoses originate from cells of the chondrocyte lineage. Ongoing work is focused on developing therapeutic approaches for treating the disease. Dr. Esko is one of The MHE Research Foundation members of the Scientific and Medical  Board A co-chaired the first conference sponsored by the MHE Research Foundation.  

Maurizio Pacifici, Ph.D. - Director of Research, Department of Orthopedic Surgery - CHOP

The mechanisms by which exostoses form along the growth plates of long bones and other skeletal elements remain largely unclear. Since the majority of HME patients carry loss-of-function mutations in Ext1 or Ext2, other groups previously created heterozygous null Ext1 (Ext1+/-) mice that were expected to display traits of HME patients.

Surprisingly, the mutant mice did not completely mimic the human phenotype. Exostosis-like masses were observed in 10-20% of the mice only, and the ectopic masses were rather small and atypical in organization and were limited to the ribs. Based on immunohistochemical evidence that human exostoses contain far less heparan sulfate (HS) than would be expected of a heterozygous Ext mutation (about 50% of control levels), we reasoned that mice producing lower amounts of HS chains may be able to mimic the human condition more closely. Thus, we created and examined double heterozygous Ext1+/-/ Ext2+/- mice. Indeed, the double hets mice did display stereotypic exostoses along their long bones that were characterized by a distal cartilaginous cap followed by a pseudo growth plate and were oriented at a 90 degree angle with respect to the long axis of the 
long bones.

We even observed osteochondromas masses at other locations. The data strongly indicate that exostosis formation and organization are intimately sensitive to, and dependent on, HS production and/or content and that frequency of exostosis formation can be increased by progressive decreases in Ext expression. Data from an additional mouse model of HME and data from mesenchymal cell cultures that provide important insights into the mechanisms of exostosis induction and formation. Oub labs on going work is focused on developing therapeutic approaches for treating the disease.

Matthew J. Hilton: University of Rochester Medical Center Lab - Director of Histology, Biochemistry, and Molecular Imaging (HBMI) Core, CMSR

Most of the bones in the vertebrate skeleton arise from a cartilage template during embryogenesis. This process, known as endochondral ossification, begins with the differentiation of condensed mesenchymal stem cells (MSCs) into chondroprogenitors (immature cartilage cells) and osteoprogenitors (immature bone cells). Both the chondroprogenitor and osteoprogenitor cells undergo a coupled proliferation and differentiation program ultimately leading to the formation of mature cartilage and bone.  Various genetic studies have demonstrated that Ihh, Pthrp, BMPs, FGFs, and canonical Wnt signaling pathways are required at multiple stages of normal cartilage and bone development. Deregulation of these signaling circuits during development are a primary cause for a variety of skeletal dysplasias, as well as, age related cartilage and bone pathologies.

A long-term interest of the Hilton lab is to uncover the molecular circuitry regulating lineage commitment, proliferation, and differentiation of MSCs and maturing chondrocytes. My laboratory uses genetic mouse models and primary cell culture techniques coupled with biochemistry to answer questions regarding MSC self-renewal/differentiation, chondrogenesis, and chondrocyte maturation. Recently my lab has generated novel data from a variety of Notch gain and loss-of-function mutant mice demonstrating that Notch signaling pathway suppresses MSC differentiation and plays critical roles in regulating chondrogenesis and chondrocyte maturation. We are currently investigating the exact Notch signaling mechanisms regulating both early and late stages of these processes, as well as, determining how Notch components interact with other known signaling pathways during cartilage development and maintenance. These studies are also being extended to aid in our mechanistic understanding of both fracture repair and osteoarthritis.

Finally, the Hilton lab is continuing to investigate the molecular mechanisms responsible for a developmental bone and cartilage disorder known as Multiple Hereditary Exostoses (MHE). MHE is an autosomal dominant disease caused by mutations in either the Ext1 or Ext2 genes, subunits of the heparan sulphate co-polymerase complex. Affected individuals are diagnosed with cartilaginous bony outgrowths (exostoses) adjacent to the growth plates of endochondral bones, bowing of some bones, and short stature. Although previous studies have shown that defects in Ext1 and Ext2 lead to reduced synthesis and shortened heparan sulphate chains on cell surface proteoglycans, the exact molecular mechanisms underlying this skeletal disease are still unknown. My lab is currently examining various Ext1 conditional mutant mouse models to determine the precise cell lineage and cause of exostosis formation. Additional genetic studies are also aimed at determining the effect that loss of Ext1 function has on specific signaling pathways important during chondrocyte and osteoblast development.

Andrea Vortkamp, P.h.D - Professor Universität Duisburg-Essen Lab

Multiple Osteochondroma Syndrome (MO) is characterized by benign bone tumors that grown out oft he growth plate during childhood. In about 5% of cases they transform into malignancy. Ext1 the gene mutated in the diseases catalyzes the synthesis of Heparansulfate (HS), extracellular polyglycan chains attached to core proteins. Recently HS has been shown to regulate binding and distribution of many secreted proteins including signaling factors like Ihh, Wnts Fgfs Bmps and others. Based on findings of our group that clonal loss of heterozygosity of Ext1 provides the basis for the disease (Jones et al., 2010) we are aiming to identify the molecular causes (altered growth factor signaling and cell adhesion) of MO. In addition, using Ihh binding as an example we investigate how the sulfation pattern of the HS chains regulates release, distribution and signaling activity of growth factors in differentiating chondrocytes and in the bone marrow stem cell niche. Towards this aim we are combining in vivo analyses in mouse mutants of various HS modifying enzymes with biochemical and bioinformatics studies.

Marion Kuche-Gullberg, Ph.D. Characterization of enzymes involved in heparan sulfate biosynthesis:

Our area of interest is the structure and function of heparan sulfate (HS). HSs play dynamic functional roles in a diverse number of biological events related to intracellular signaling, cell-cell interactions and tissue morphogenesis.

HS execute its function by the binding to a variety of molecules including growth factors, serine protease inhibitors and extracellular matrix proteins.  The biological activities of HS largely depend on the amount and distribution of its sulfate groups that provide specific binding sites for proteins.

Our overall goal is to understand the mechanisms generating specific saccharide structures and to provide insight into the link between cell type specific expression of HS modifying enzymes and the biological function of the polysaccharide.

Our research focuses on:

1.  UDP-glucose dehydrogenase, which converts UDP-glucose to UDP-glucuronic acid providing one of the building blocks for chain elongation

2.  heparan sulfate polymerases (EXT1 and EXT2) giving rise to the polysaccharide backbone(mice with a gene trap mutation in Ext)

3.  2-O- and 6-O-sulfotransferases, incorporating sulfate groups in specific positions, generating biological active heparan sulfate.

4.  Sulfs, cell associated HS 6-O endosulfatases, that remove sulfate groups in specific positions, thus modulating HS dependent growth factor signaling.

Henry H. Roehl, Ph.D. - Roehl Lab Department of Biomedical Science, The University of Sheffield, United Kingdom

The Roehl laboratory  focuses on the role of heparin sulphate proteoglycans (HSPGs) during development of the zebrafish. Although HSPGs are ubiquitous structural components of the extracellular matrix, they are also thought to play very specific roles in cell-cell signalling during development. The disaccharide repeats that make up the heparan chains come in 32 different varieties making heparan sulphate the most information-dense biopolymer found in nature. Binding studies and X-ray crystallography have identified many specific interactions between oligosaccharides and secreted proteins. Mutational analysis of genes involved with proteoglycan synthesis has shown that Wingless, Decapentaplegic, Fibroblast Growth Factor and Hedgehog signalling pathways all depend on proteoglycans at different times during Drosophila development. These data together have led to the hypothesis that different HSPGs have highly specialized roles including limiting or facilitating signal diffusion, blocking signal degradation and modulating signal/receptor complex formation.

Our work in this field began with the positional cloning of a small family of zebrafish mutants that all have similar phenotypes suggesting that their gene products interact or are in the same pathway. These genes, pinscher (pic/papst1), boxer (box/extl3) and dackel(dak/ext2), are all required for development of the pectoral fins, sorting of the retinotectal projections and morphogenesis of the skeleton. This cloning project has been a collaboration between three groups (Chi-Bin Chien, U. of Utah; Robert Geisler, M.P.I. Tuebingen; Henry Roehl, U. of Sheffield). Together, we have found that box and dak encode glycosyltransferases responsible for synthesis of the heparin sugar chain (EXTL3 and EXT2 respectively), and pic encodes a sulphur transporter that is involved with the sulphation of all proteogycans (PAPST1). These finding have allowed us to begin to address the functional requirements of HSPGs during zebrafish development.

Recently we have turned our attention to the role of HSPGs play in a disease called Hereditary Multiple Exostoses (HME). HME is an autosomal dominant disorder that affects 1 in 50,000 among the general population. Patients with HME have a short stature and develop numerous cartilage-capped tumours (called exostoses or osteochondromas) from the growth plates of their longbones. Mutations in human EXT2 account for a large percentage of the cases of this disease. While osteochondromas are normally benign, they can lead to complications and patients have a 1-2% risk of developing chondrosarcoma or osteosarcoma. The dominant and sporadic nature of tumour formation in HME patients has led to the proposal of two genetic models. Osteochondromas may arise from a loss of heterozygosity (LOH) at one of the EXT loci in a developing chondrocyte resulting in unregulated growth and clonal expansion. In support of this model, somatic mutations or aneuploidy have been found in 3 out of 46 osteochondromas analysed. The alternative model is that reduced EXT gene dose results in a structural change that allows chondrocytes to occasionally escape normal developmental constraints to give rise to an osteochondroma.

Kevin Jones, MD - Researcher at The University of Utah

Kevin B. Jones is a physician-scientist who provides diagnostic evaluation
and surgical management of bone and soft-tissue tumors in children and
adults. He sees patients at Primary Children's Hospital and the Huntsman
Cancer Institute, both at the University of Utah in Salt Lake City, Utah.
After studying literature at Harvard and medicine at the Johns Hopkins,
Kevin completed an orthopaedic surgery residency at the University of Iowa and musculoskeletal oncology fellowship at Mount Sinai, Princess Margaret, and Sick Kids Hospitals in the University of Toronto. He came to Utah to study mouse genetic modeling with the Nobel Laureate, Mario Capecchi.


The Jones lab at the Huntsman Cancer Institute is focused on the development and study of mouse genetic models of human connective tissue neoplasms. They have produced genetic mouse models of a number of rare cancer types, including synovial sarcoma, clear cell sarcoma, alveolar soft part sarcoma, and peripheral chondrosarcoma. Kevin began what became the first genetic mouse model of efficient osteochondromagenesis (by inefficient conditional clonal disruption of Ext1) as a resident in Iowa, in the Val Sheffield Genetics Laboratory, finishing the initial paper describing the mouse after arriving in Utah. In his spare time, Kevin also writes about the challenges of physician-patient communication amidst the ever-present uncertainties inherent to medicine.

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