Research authored by Dr.Vortkamp
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List of Publications via PubMed
(NIH National Library of Medicine)
Ihh signaling in the growth plate.

Abstract 2005 MHE conference

Andrea Vortkamp

Centre for Medical Biotechnology, Department of Developmental
Biology, University Duisburg-Essen, 45117 Essen, Germany

Endochondral ossification is a multi step process during which a cartilage template is successively replaced by bone tissue.
Chondrocytes in the cartilage anlagen undergo several steps of differentiation until they become terminal hypertrophic and are
subsequently replaced by bone.

The secreted growth factor Indian hedgehog (Ihh) is expressed in a distinct population of chondrocytes that undergo
hypertrophic differentiation. Ihh interacts with a second secreted molecule, Parathyroid Hormone related Protein (PTHrP),
expressed in the distal ends of the cartilage elements in a negative feedback mechanism to regulate the onset of hypertrophic
differentiation.Analyzing a mouse line carrying a hypomorphic allele of Ext1,a glycosytransferase necessary for the synthesis of
heparan sulfates (HS), we have recently shown that HS negatively regulates the propagation of the Ihh signal in a concentration
dependent manner. Our data strongly indicate that Ihh acts as a long range morphogen directly inducing the expression of

To further investigate the interaction between Ihh and PTHrP, we have started to analyze the role of the zinc finger transcription
factor Gli3, which acts downstream of hedgehog signals in other organs. Ihh;Gli3 double mutants indicate that Gli3 acts as a
repressor downstream of Ihh in regulating chondrocyte proliferation and the expression of PTHrP, and, thus, the onset of
hypertrophic differentiation.

Furthermore, our studies identified a new function of the Ihh/Gli3 system in negatively regulating the differentiation of distal, low
proliferating (zone) into central, high proliferating (zone II) chondrocytes.
Whereas the domain of zone II chondrocytes is determined by the level of PTHrP, the transition of zone I into zone II
chondrocytes is regulated by Gli3R independent of PTHrP.
About Dr. Vortkamp's research
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Multiple Hereditary Exostoses / Multiple

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2009 Conference abstract
Molecular Characterization of Osteochondroma Development in Mice

Virginia Piombo, Kevin B. Jones, Charles Searby, Gail Kurriger, Florian Grabellus, Peter Roughley, Jose A. Morcuende, Joseph A.
Buckwalter, Mario R. Capecchi, Val C. Sheffield, Andrea Vortkamp

Hereditary multiple exostoses syndrome (HME) is a dominant inherited human disorder characterized by short stature and
exostoses (osteochondromas) of the growth plat. HME results from mutations in EXT1 or EXT2, which encode
glycosyltransferases necessary for the synthesis of heparansulfate (HS). Investigation of hypomorphic Ext1 (Ext1gt/gt) mice
demonstrated that reduced HS levels lead to an increased range of Ihh signaling and consequently to a delay in hypertrophic
differentiation of chondrocytes. Here we have analyzed chimeric mice, in which clones of Ext1 mutant cells have been induced by
Doxycycline-dependent exon inversions. We show that, in contrast to heterozygous deletion of Ext1, these mice develop
exostoses of the axial skeleton. On morphological level later stages of exostoses resemble that of human patients with a bony
shaft connected to the bone of the affected skeletal element. On molecular level the en of chondrocyte markers indicated that
the cell organization of the cartilaginous cap of the osteochondroma mimics that of the of the growth plate. Analysis of early
exostoses stages revealed that the origin of the osteochondroma is an early chondrocyte. We have investigated the genotype
of the osteochondroma cells by genomic PCR of small clones of cells. We found the majority of cells to be homozygous for the
mutant allele. These are also negative for the production of HS indicaing that loss of heterozygosity is required for
osteochondroma development. Nevertheless we found a subset of wildtype cells in early exostoses stages indicating that these
cells might be incorporated into the osteochondroma tissue.
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