Dr. Alman serves on the Scientific and Medical Advisory Board of the MHE Research Foundation
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List of Publications via PubMed
(NIH National Library of Medicine)
List of Publications via PubMed
(NIH National Library of Medicine)
P53 and Rb in Cartilage Tumours in Mice
Abstract 2005 MHE Conference
Aneta Stojanovski, Louisa Ho, and Benjamin Alman
The Program in Developmental Biology and Division of Orthopaedic Surgery, The Hospital for Sick Children Toronto,
Ontario Canada
Chondrosarcomas can arise from being cartilage lesions, such as enchondromas and osteochondromas.
In enchondromatosis, there is a high rate of malignant change, reported to be as high as 50% in cases of Mafucci syndrome.
Cytogenetic and mutational analysis studies identified mutations or deletions in p53 or Rb in roughly one third of
chondrosarcomas. As such, we examined the role of these tumor suppressor genes using a mouse model of enchondromatosis.
We crossed p53 and Rb knockout mice with mice overexpressing Gli2 driven by the type II collagen regulatory elements. Mice were
sacrificed and limbs analyzed using histology, Safranin-O staining, type X collagen immunohistochemistry, proliferation rate and
apoptosis rate. Larger, hypercellular, cartilaginous lesions containing pleomorphic cells arose in the Gli2;p53+/-, at an increasing
incidence starting at 2 months of age. By 8 months, 75% of these mice developed these larger lesions. This was associated with
an increase in cell proliferation. Gli2;Rb+/- mice also developed these larger lesions, but only at 8 months of age.
Examination of the fetal limbs showed an expanded growth plate, involving all zones in the Gli2;p53-/- mice, compared to the
other genotypes.P53 deficiency modulates the effect of overexpression of Gli2 in chondrocytes, resulting in a change in the growth
plate and the development of larger, hypercellular cartilage lesions, perhaps by increasing the number of chondrocyte cells in the
growth plate. This data also suggests that tumor suppressor genes play a role in cartilaginous neoplasia.
Abstract 2005 MHE Conference
Aneta Stojanovski, Louisa Ho, and Benjamin Alman
The Program in Developmental Biology and Division of Orthopaedic Surgery, The Hospital for Sick Children Toronto,
Ontario Canada
Chondrosarcomas can arise from being cartilage lesions, such as enchondromas and osteochondromas.
In enchondromatosis, there is a high rate of malignant change, reported to be as high as 50% in cases of Mafucci syndrome.
Cytogenetic and mutational analysis studies identified mutations or deletions in p53 or Rb in roughly one third of
chondrosarcomas. As such, we examined the role of these tumor suppressor genes using a mouse model of enchondromatosis.
We crossed p53 and Rb knockout mice with mice overexpressing Gli2 driven by the type II collagen regulatory elements. Mice were
sacrificed and limbs analyzed using histology, Safranin-O staining, type X collagen immunohistochemistry, proliferation rate and
apoptosis rate. Larger, hypercellular, cartilaginous lesions containing pleomorphic cells arose in the Gli2;p53+/-, at an increasing
incidence starting at 2 months of age. By 8 months, 75% of these mice developed these larger lesions. This was associated with
an increase in cell proliferation. Gli2;Rb+/- mice also developed these larger lesions, but only at 8 months of age.
Examination of the fetal limbs showed an expanded growth plate, involving all zones in the Gli2;p53-/- mice, compared to the
other genotypes.P53 deficiency modulates the effect of overexpression of Gli2 in chondrocytes, resulting in a change in the growth
plate and the development of larger, hypercellular cartilage lesions, perhaps by increasing the number of chondrocyte cells in the
growth plate. This data also suggests that tumor suppressor genes play a role in cartilaginous neoplasia.
| Dr. Alman's research |
5th Annual International Pediatric Orthopaedic Symposium (IPOS) presented by the American Academy of Orthopaedic
Surgeons (AAOS) and Pediatric Orthopaedic Society of North America (POSNA) was held in Orlando Florida from Dec 3-7, 2008.
During this symposium there was a workshop held on Dec 5, 2008 relating to the surgical needs of children with MHE. This session
was be moderated by Dr. Benjamin Alman. Our foundation would like to extend its thanks to Dr. Alman for all the support he has
shown to our foundation and MHE over the years.
Dec 2-5, 2009 held in Orlando Florida
6th International Pediatric Orthopaedic Symposium (IPOS)
If you are an Orthopaedic Surgeon and are interested in registering for this years IPOS meeting, there will be a session on Benign &
Malignant bone tumors moderated by Dr. Vernon Tolo presenting during this session are Dr. Alman, Dr. Crawford and
Dr. Dormans. A session will also be held on limb length inequality, diagnosis and management. Please Click Here for registration
information, presenters & other sessions beheld during IPOS
Surgeons (AAOS) and Pediatric Orthopaedic Society of North America (POSNA) was held in Orlando Florida from Dec 3-7, 2008.
During this symposium there was a workshop held on Dec 5, 2008 relating to the surgical needs of children with MHE. This session
was be moderated by Dr. Benjamin Alman. Our foundation would like to extend its thanks to Dr. Alman for all the support he has
shown to our foundation and MHE over the years.
Dec 2-5, 2009 held in Orlando Florida
6th International Pediatric Orthopaedic Symposium (IPOS)
If you are an Orthopaedic Surgeon and are interested in registering for this years IPOS meeting, there will be a session on Benign &
Malignant bone tumors moderated by Dr. Vernon Tolo presenting during this session are Dr. Alman, Dr. Crawford and
Dr. Dormans. A session will also be held on limb length inequality, diagnosis and management. Please Click Here for registration
information, presenters & other sessions beheld during IPOS
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Benjamin A. Alman
Multiple Hereditary Exostosis and Hedgehog Signaling: Implications for Novel Therapies
The Journal of Bone and Joint Surgery. Am., Jul 2009; 91: 63 - 67.
Multiple Hereditary Exostosis and Hedgehog Signaling: Implications for Novel Therapies
The Journal of Bone and Joint Surgery. Am., Jul 2009; 91: 63 - 67.
Questions to the Scientific & Medical Advisory Board,
Please use the contact Scientific & Medical Advisory Board Tab or you may email directly
AdvisoryBoard@mheresearchfoundation.org
Please use the contact Scientific & Medical Advisory Board Tab or you may email directly
AdvisoryBoard@mheresearchfoundation.org
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Have a Question or Comments for the Board of Directors,
Please use the contact Board of Directors Tab or General enquiries can be emailed to
Boardofdirectors@mheresearchfoundation.org
Please use the contact Board of Directors Tab or General enquiries can be emailed to
Boardofdirectors@mheresearchfoundation.org
| ||||||
2009 conference abstract
Gli2 and p53 cooperate to regulate IGFBP-3 mediated chondrocyte apoptosis in the progression from benign to
malignant cartilage tumors.
Louisa Ho*1,2,3, Aneta Stojanovski*1,2,3, Heather Whetstone*1, Qing Xia Wei1,2, Elaine Mau1, Jay S. Wunder2, and Benjamin
Alman1,3,4
1Program in Developmental and Stem Cell Biology, Hospital for Sick Children, University of Toronto, Toronto ON, M5G 1L7.
2Samuel Lunenfeld Research Institute, Mount Sinai Hospital, University of Toronto, Toronto, ON. 3 Division of Orthopaedic
Surgery, Department of Surgery, and Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON.
*These authors contributed equally to this work.
e-mail: benjamin.alman@sickkids.ca.
Clinical evidence suggests that benign cartilage lesions can progress to malignant chondrosarcoma, but the molecular events in this
progression are unknown. Mice that develop benign cartilage lesions due to overexpression of Gli2 in chondrocytes developed
lesions similar to chondrosarcomas when also deficient in p53. Gli2 overexpression and p53 deficiency had opposing effects on
chondrocyte differentiation, but had additive effects negatively regulating apoptosis. Regulation of Igfbp3 expression and IGF
signaling by Gli and p53 integrated their effect on apoptosis. Treatment of human chondrosarcomas or fetal mouse limbs explants
with IGFBP3 or by blocking IGF increased the apoptosis rate, and mice expressing Gli2 developed substantially fewer tumors when
also deficient for Igf2. IGF signaling meditated apoptosis regulates the progression to malignant chondrosarcoma.
Although molecular mechanisms responsible for the progression of benign to malignant tumors of epithelial origin have been
identified, they have not been demonstrated in mesenchymal tumors. Here we used a mouse model of enchondromatosis to show
that p53 deficiency can cause chondrosarcomas to arise from benign lesions. An unexpected role for IGFBP3 in this progression
was found. Human cartilage tumors have low levels of IGFBP3 expression compared to normal chondrocytes, with
chondrosarcomas having lower levels than benign lesions, suggesting IGFBP3 level as a prognostic factor in cartilage tumors.
Furthermore, IGFBP3 treatment or IGF signaling blockade increased chondrosarcoma apoptosis, suggesting a therapeutic approach
to chondrosarcomas, a tumor for which there is no universally effective chemotherapy.
Gli2 and p53 cooperate to regulate IGFBP-3 mediated chondrocyte apoptosis in the progression from benign to
malignant cartilage tumors.
Louisa Ho*1,2,3, Aneta Stojanovski*1,2,3, Heather Whetstone*1, Qing Xia Wei1,2, Elaine Mau1, Jay S. Wunder2, and Benjamin
Alman1,3,4
1Program in Developmental and Stem Cell Biology, Hospital for Sick Children, University of Toronto, Toronto ON, M5G 1L7.
2Samuel Lunenfeld Research Institute, Mount Sinai Hospital, University of Toronto, Toronto, ON. 3 Division of Orthopaedic
Surgery, Department of Surgery, and Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON.
*These authors contributed equally to this work.
e-mail: benjamin.alman@sickkids.ca.
Clinical evidence suggests that benign cartilage lesions can progress to malignant chondrosarcoma, but the molecular events in this
progression are unknown. Mice that develop benign cartilage lesions due to overexpression of Gli2 in chondrocytes developed
lesions similar to chondrosarcomas when also deficient in p53. Gli2 overexpression and p53 deficiency had opposing effects on
chondrocyte differentiation, but had additive effects negatively regulating apoptosis. Regulation of Igfbp3 expression and IGF
signaling by Gli and p53 integrated their effect on apoptosis. Treatment of human chondrosarcomas or fetal mouse limbs explants
with IGFBP3 or by blocking IGF increased the apoptosis rate, and mice expressing Gli2 developed substantially fewer tumors when
also deficient for Igf2. IGF signaling meditated apoptosis regulates the progression to malignant chondrosarcoma.
Although molecular mechanisms responsible for the progression of benign to malignant tumors of epithelial origin have been
identified, they have not been demonstrated in mesenchymal tumors. Here we used a mouse model of enchondromatosis to show
that p53 deficiency can cause chondrosarcomas to arise from benign lesions. An unexpected role for IGFBP3 in this progression
was found. Human cartilage tumors have low levels of IGFBP3 expression compared to normal chondrocytes, with
chondrosarcomas having lower levels than benign lesions, suggesting IGFBP3 level as a prognostic factor in cartilage tumors.
Furthermore, IGFBP3 treatment or IGF signaling blockade increased chondrosarcoma apoptosis, suggesting a therapeutic approach
to chondrosarcomas, a tumor for which there is no universally effective chemotherapy.
| Photo's taken during the Third International MHE Research Conference |
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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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