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Profiling of hereditary and solitary osteochondromas and peripheral chondrosarcomas on genomic, gene expression
and protein level.
Abstract 2005 MHE Conference
L. Hameetman, A.M. Cleton-Jansen, G. David, J.V.M.G. Bovee,
P.C.W. Hogendoorn. Department of Pathology Leiden University Medical Center,
Leiden The Netherlands and University of Leuven, Belgium
Osteochondroma is a cartilage capped benign bony neoplasm on the outer surface of bones preformed by endochondral
ossification. The cartilage cap of osteochondroma histologically resembles the morphological organization of an epiphyseal
growth plate. A small percentage osteochondromas transform towards their malignant counter part, secondary peripheral
chondrosarcoma. For Multiple Osteochondromas EXT1 located at 8q24 was shown to act as tumor suppressor gene in tumours
of EXT1 mutant patients.
We demonstrate that in hereditary tumors EXT expression is correlated with mutation status of the patient. Furthermore,
EXT1, but not EXT2, is down-regulated in sporadic tumors, where 8q24 loss is a frequent phenomenon, but mutations or
promoter hypermethylation are not found till now.
EXT genes are involved in biosynthesis of heparan sulphate proteoglycans (HSPGs). Immunohistochemical evaluation of a series
(n=70) of both hereditary and solitary tumors revealed intracellular accumulation of HSPG core proteins and of shorter or less
complex HS chains, in contrast to the extracellular expression of these molecules found in growth plates. HSPGs are involved in
several growth signaling pathways, including in the negative feedback loop of the Indian Hedgehog (IHH) and parathyroid
hormone–like hormone (PTHLH).PTHLH signaling is absent in osteochondromas, but reactivated upon malignant transformation
towards chondrosarcoma.Disturbed expression of IHH signaling molecules has also been implicated in osteochondroma.
With quantitative RT-PCR we were able to demonstrate similar expression levels of IHH signaling in osteochondromas as
compared to the growth plate. A gradual decrease in expression of IHH signaling molecules was observed with increasing
malignancy, suggesting that IHH signaling is inactived and PTHLH signaling is IHH-independent in chondrosarcomas. cDNA
expression profiling and immunohistochemical studies suggest that TGF--mediated proliferative signaling is upregulated in
high-grade chondrosarcomas. TGF- is a good candidate to regulate PTHLH signaling in high-grade tumors.Chondrosarcoma
progression is further accompanied by down-regulation of energy metabolism-related genes and upregulation of the proto-
oncogene jun B.
Dysplasia Epiphysealis Hemimelica (DEH, Trevor's disease) and metachondromatosis (MC) are considered in the differential
diagnosis of solitary and hereditary osteochondromas. In a comparative study between DEH, MC and osteochondroma we were
able to demonstrate that histologically DEH differs from conventional osteochondroma, while MC-related lesions do not. With
qPCR we show that in contrast to osteochondroma, MC and DEH still express the EXT genes and immunohistochemical analysis
showed that EXT downstream pathways are active. These results indicate that DEH and MC are indeed different entities and
that so far unknown molecular defects in these lesions do not affect EXT signaling.
and protein level.
Abstract 2005 MHE Conference
L. Hameetman, A.M. Cleton-Jansen, G. David, J.V.M.G. Bovee,
P.C.W. Hogendoorn. Department of Pathology Leiden University Medical Center,
Leiden The Netherlands and University of Leuven, Belgium
Osteochondroma is a cartilage capped benign bony neoplasm on the outer surface of bones preformed by endochondral
ossification. The cartilage cap of osteochondroma histologically resembles the morphological organization of an epiphyseal
growth plate. A small percentage osteochondromas transform towards their malignant counter part, secondary peripheral
chondrosarcoma. For Multiple Osteochondromas EXT1 located at 8q24 was shown to act as tumor suppressor gene in tumours
of EXT1 mutant patients.
We demonstrate that in hereditary tumors EXT expression is correlated with mutation status of the patient. Furthermore,
EXT1, but not EXT2, is down-regulated in sporadic tumors, where 8q24 loss is a frequent phenomenon, but mutations or
promoter hypermethylation are not found till now.
EXT genes are involved in biosynthesis of heparan sulphate proteoglycans (HSPGs). Immunohistochemical evaluation of a series
(n=70) of both hereditary and solitary tumors revealed intracellular accumulation of HSPG core proteins and of shorter or less
complex HS chains, in contrast to the extracellular expression of these molecules found in growth plates. HSPGs are involved in
several growth signaling pathways, including in the negative feedback loop of the Indian Hedgehog (IHH) and parathyroid
hormone–like hormone (PTHLH).PTHLH signaling is absent in osteochondromas, but reactivated upon malignant transformation
towards chondrosarcoma.Disturbed expression of IHH signaling molecules has also been implicated in osteochondroma.
With quantitative RT-PCR we were able to demonstrate similar expression levels of IHH signaling in osteochondromas as
compared to the growth plate. A gradual decrease in expression of IHH signaling molecules was observed with increasing
malignancy, suggesting that IHH signaling is inactived and PTHLH signaling is IHH-independent in chondrosarcomas. cDNA
expression profiling and immunohistochemical studies suggest that TGF--mediated proliferative signaling is upregulated in
high-grade chondrosarcomas. TGF- is a good candidate to regulate PTHLH signaling in high-grade tumors.Chondrosarcoma
progression is further accompanied by down-regulation of energy metabolism-related genes and upregulation of the proto-
oncogene jun B.
Dysplasia Epiphysealis Hemimelica (DEH, Trevor's disease) and metachondromatosis (MC) are considered in the differential
diagnosis of solitary and hereditary osteochondromas. In a comparative study between DEH, MC and osteochondroma we were
able to demonstrate that histologically DEH differs from conventional osteochondroma, while MC-related lesions do not. With
qPCR we show that in contrast to osteochondroma, MC and DEH still express the EXT genes and immunohistochemical analysis
showed that EXT downstream pathways are active. These results indicate that DEH and MC are indeed different entities and
that so far unknown molecular defects in these lesions do not affect EXT signaling.
Research authored by Dr. Hogendoorn
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List of Publications via PubMed
(NIH National Library of Medicine)
List of Publications via PubMed
(NIH National Library of Medicine)
|
Press Release 03 / 06 / 07 4pm Eastern time
JNCI Journal of the National Cancer Institute 2007 99(5):396-406; doi:10.1093/jnci/djk067
To read Journal Full text publication Click Here
EXT1 Gene Influences Formation of Nonhereditary Benign Bone Tumors
Mutations in a gene known as EXT1 cause Multiple Osteochondromas, a rare hereditary disorder that results in the formation of
benign cartilage-covered bone tumors. Now scientists have shown that EXT1 is also involved in the development of
nonhereditary osteochondromas, the more common form of the disease.
Liesbeth Hameetman of Leiden University Medical Center in The Netherlands, and colleagues examined eight nonhereditary
osteochondromas to determine whether EXT1 acts as a tumor-suppressing gene in nonhereditary osteochondromas in the
same way it does in hereditary ones. Mutations or deletions of tumor suppressor genes increased the likelihood of a cell
becoming a tumor cell, but both copies of the gene had to be affected for this to happen.
In seven of the eight osteochondromas, both copies of EXT1 were deleted; these deletions occurred only in the cartilage cap of
the one osteochondroma that was examined in detail. Previous studies demonstrated that the cartilage cap was formed of
tumor tissue, but it was unknown whether other parts of the osteochondromas—the bony stalk and the connective tissue—
were as well. The authors conclude that EXT1 acts as a tumor suppressor gene in the cartilage of nonhereditary
osteochondromas.
“Our finding that the cartilage cap is the only [tumor] component of osteochondroma revives long-standing debate about the
cell origin of osteochondromas,” the authors write.
The MHE Research Foundation would like to thank Dr. Hogendoorn and his colleagues for all their long standing research efforts.
These research findings have paramount importance to the field of MHE / MO / HME research. MHERF would also like to thank
Dr. Hogendoorn for always staying in such close contact with our organization and for all his support. Also for being given this
opportunity to be the first organization besides the JNCI Journal of the National Cancer Institute to help announce these
research findings.
Contact: Pancras Hogendoorn, Leiden University Medical Center
JNCI Journal of the National Cancer Institute 2007 99(5):396-406; doi:10.1093/jnci/djk067
To read Journal Full text publication Click Here
EXT1 Gene Influences Formation of Nonhereditary Benign Bone Tumors
Mutations in a gene known as EXT1 cause Multiple Osteochondromas, a rare hereditary disorder that results in the formation of
benign cartilage-covered bone tumors. Now scientists have shown that EXT1 is also involved in the development of
nonhereditary osteochondromas, the more common form of the disease.
Liesbeth Hameetman of Leiden University Medical Center in The Netherlands, and colleagues examined eight nonhereditary
osteochondromas to determine whether EXT1 acts as a tumor-suppressing gene in nonhereditary osteochondromas in the
same way it does in hereditary ones. Mutations or deletions of tumor suppressor genes increased the likelihood of a cell
becoming a tumor cell, but both copies of the gene had to be affected for this to happen.
In seven of the eight osteochondromas, both copies of EXT1 were deleted; these deletions occurred only in the cartilage cap of
the one osteochondroma that was examined in detail. Previous studies demonstrated that the cartilage cap was formed of
tumor tissue, but it was unknown whether other parts of the osteochondromas—the bony stalk and the connective tissue—
were as well. The authors conclude that EXT1 acts as a tumor suppressor gene in the cartilage of nonhereditary
osteochondromas.
“Our finding that the cartilage cap is the only [tumor] component of osteochondroma revives long-standing debate about the
cell origin of osteochondromas,” the authors write.
The MHE Research Foundation would like to thank Dr. Hogendoorn and his colleagues for all their long standing research efforts.
These research findings have paramount importance to the field of MHE / MO / HME research. MHERF would also like to thank
Dr. Hogendoorn for always staying in such close contact with our organization and for all his support. Also for being given this
opportunity to be the first organization besides the JNCI Journal of the National Cancer Institute to help announce these
research findings.
Contact: Pancras Hogendoorn, Leiden University Medical Center
| Pancars Hogendoorn M.D., Ph.D. research |
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Questions to the Scientific & Medical Advisory Board,
Please use the contact Scientific & Medical Advisory Board Tab or you may email directly
AdvisoryBoard@mheresearchfoundation.org
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The presence of dental problems has been communicated to us by some MO patients, but as far as we know, there are no
medical data published that would confirm this observation. As problems with teeth might severely affect not only the self
esteem but also general health, hence we recognize that dental health in MO patients needs to be investigated.
The MHE Research Foundation with the support and collaboration of Pancras Hogendoorn, M.D., Ph.D. and Malgorzata Wiweger,
Ph.D. from the Leiden University Medical Center(LUMC) The Netherlands a questionnaire has been designed that could be
answered without need of seeing any dentist or other medical professionals. We hope that this survey will contribute to better
understanding of the MO disorder and improve the quality of care given to MO patients.
The research team aims to make the results publicly available in a form of an article published in a scientific journal, so basic
researchers; medical professionals and people affected by MO will be able to read the results.
medical data published that would confirm this observation. As problems with teeth might severely affect not only the self
esteem but also general health, hence we recognize that dental health in MO patients needs to be investigated.
The MHE Research Foundation with the support and collaboration of Pancras Hogendoorn, M.D., Ph.D. and Malgorzata Wiweger,
Ph.D. from the Leiden University Medical Center(LUMC) The Netherlands a questionnaire has been designed that could be
answered without need of seeing any dentist or other medical professionals. We hope that this survey will contribute to better
understanding of the MO disorder and improve the quality of care given to MO patients.
The research team aims to make the results publicly available in a form of an article published in a scientific journal, so basic
researchers; medical professionals and people affected by MO will be able to read the results.
| New Research Project Open Starting July 15, 2009 MHE / MO Dental Questionnaire |
2009 Conference abstract
Primary Cilia Organization Orchestrating Cell Polarity in the Growth Plate and its Loss in Osteochondroma
C. de Andrea, M. Wiweger, F. Prins, J.V.M.G. Bovee, S. Romeo, P.C.W. Hogendoorn
The growth plate (GP) is a cartilaginous template for the elongation of long bones. In its regulation heparan sulphate
proteoglycan (HSPG) and primary cilia (PC) play a role. Impaired HSPG biosynthesis is associated with osteochondroma (OC)
formation. PC function as cell’s antennas that receive and transduce mechanical and chemical signals from the surrounding cells
and the extracellular matrix. We evaluated the organization of PC in GP and OC and its relation with cell polarity. The
constituting cells of the human GPs (n=5) and OCs (n=5) had PC as documented by confocal microscopy using anti-acetylated
α-tubulin antibody. The PC assembly was similar in both as judged by electron microscopy and the immunolocalization of KIF3A
motor protein and γ-tubulin. The PC organization in the GP reflected that chondrocytes non-polarized (resting chondrocytes)
became polarized (proliferating and hypertrophic chondrocytes) orienting the cilium parallel to the longitudinal axis of the bone.
The PC alignment formed one virtual axis which crossed the center of column of chondrocytes. The ciliary axes showed the
polarity axis of the GP. In OC, PC were randomly located in the central or in the lateral-medial region of the cells related to the
growth axis of the tumor. The PC organization in OC reflected loss of cell polarity that seemed to be a key event and might
indicate impaired cell movement or problems in cell-matrix interaction. We also demonstrated the dynamicity of PC whose
presence/absence was correlated with the cell cycle.
Primary Cilia Organization Orchestrating Cell Polarity in the Growth Plate and its Loss in Osteochondroma
C. de Andrea, M. Wiweger, F. Prins, J.V.M.G. Bovee, S. Romeo, P.C.W. Hogendoorn
The growth plate (GP) is a cartilaginous template for the elongation of long bones. In its regulation heparan sulphate
proteoglycan (HSPG) and primary cilia (PC) play a role. Impaired HSPG biosynthesis is associated with osteochondroma (OC)
formation. PC function as cell’s antennas that receive and transduce mechanical and chemical signals from the surrounding cells
and the extracellular matrix. We evaluated the organization of PC in GP and OC and its relation with cell polarity. The
constituting cells of the human GPs (n=5) and OCs (n=5) had PC as documented by confocal microscopy using anti-acetylated
α-tubulin antibody. The PC assembly was similar in both as judged by electron microscopy and the immunolocalization of KIF3A
motor protein and γ-tubulin. The PC organization in the GP reflected that chondrocytes non-polarized (resting chondrocytes)
became polarized (proliferating and hypertrophic chondrocytes) orienting the cilium parallel to the longitudinal axis of the bone.
The PC alignment formed one virtual axis which crossed the center of column of chondrocytes. The ciliary axes showed the
polarity axis of the GP. In OC, PC were randomly located in the central or in the lateral-medial region of the cells related to the
growth axis of the tumor. The PC organization in OC reflected loss of cell polarity that seemed to be a key event and might
indicate impaired cell movement or problems in cell-matrix interaction. We also demonstrated the dynamicity of PC whose
presence/absence was correlated with the cell cycle.
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Click here to verify.# HON Conduct 282463 and is the patient support link on the US Government Genetics Home Reference (http://ghr.nlm.nih.gov)
website, also linked for Patient Information on The Diseases Database a cross-referenced index of human disease, as well as 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
The MHE Research Foundation is proud to be working with the EuroBoNeT consortium, a European Commission granted Network of Excellence for
studying the pathology and genetics of bone tumors.
studying the pathology and genetics of bone tumors.
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