|
Roland Leach, PH.D.
Tibia Dyschondroplasia: An Example of Defective Hedgehog Signaling?
Abstract 2005 MHE Conference
R. M. Leach, Jr., F. M. R. McAvoy, M. Shahnazari, and S. N. Krzysik
Department of Poultry Science, The Pennsylvania State University, University Park, Pa.
Tibial Dyschondroplasia (TD) is a skeletal disease common to rapidly - -growing young avians.
This condition is characterized as a mass of avascular cartilage in the epiphyseal growth plate of tibiotarsus and
tarsalmetatarsus.
The lesion occurs spontaneously with an incidence ranging from 10-90%. Exposure to dithiocarbamates induces a high
incidence of the lesion without impairing growth rate.
The lesion appears to initiate in the prehypertrophic zone adjacent to the perichondrium, resulting in a triangular lesion of
variable size. The chondrocytes in the lesion fail to achieve complete hypertrophy and undergo apoptosis. This latter
characteristic has severely impaired attempts to identify the metabolic defect responsible for this skeletal disease.
For a number of years, we have been pursuing the hypothesis that TD occurs as a result of perturbation
in Indian Hedgehog (Ihh) signaling. This is based on the observation that Ihh, which plays a key role in skeletal physiology, is
localized in the zone where the lesion appears to be initiated.
Our first approach was to confirm this hypothesis by studying Ihh expression in cultured chondrocytes.
This approach was abandoned due to the extreme cytotoxicity of the dithiocarbamates. Since sterolization is an important
post-translational modification of hedgehog proteins, an inhibitor of cholesterol biosynthesis (a statin) was fed to young chicks
as a means of perturbing hedgehog activity. These chicks exhibited depressed growth rate and a TD-like lesion in the
prehypertrophic zone of the epiphyseal growth plate. Supplementary dietary cholesterol resulted in normal growth plate
morphology, although the growth rate depression was not reversed.
These results were exciting, but we were faced with a dilemma: which hedgehog is being inhibited?
Wu et al. (2002) have reported that both Ihh and Sonic Hedgehog (Shh) are expressed in the post-natal avian growth plate,
with Shh being expressed distal to Ihh. We have confirmed the presence of Shh in lysates of hypertrophic chondrocytes with
western blotting. The expression of two hedgehogs at different locations in the growth plate supports previous suggestions
that hedgehog proteins have dual actions in growth plate physiology.
Currently we are using immunohistochemistry, western blotting and microarray technology to identify the downstream targets
of hedgehog genes responsible for the impaired angiogenesis associated with the development of tibial dyschondroplasia.
Abstract 2005 MHE Conference
R. M. Leach, Jr., F. M. R. McAvoy, M. Shahnazari, and S. N. Krzysik
Department of Poultry Science, The Pennsylvania State University, University Park, Pa.
Tibial Dyschondroplasia (TD) is a skeletal disease common to rapidly - -growing young avians.
This condition is characterized as a mass of avascular cartilage in the epiphyseal growth plate of tibiotarsus and
tarsalmetatarsus.
The lesion occurs spontaneously with an incidence ranging from 10-90%. Exposure to dithiocarbamates induces a high
incidence of the lesion without impairing growth rate.
The lesion appears to initiate in the prehypertrophic zone adjacent to the perichondrium, resulting in a triangular lesion of
variable size. The chondrocytes in the lesion fail to achieve complete hypertrophy and undergo apoptosis. This latter
characteristic has severely impaired attempts to identify the metabolic defect responsible for this skeletal disease.
For a number of years, we have been pursuing the hypothesis that TD occurs as a result of perturbation
in Indian Hedgehog (Ihh) signaling. This is based on the observation that Ihh, which plays a key role in skeletal physiology, is
localized in the zone where the lesion appears to be initiated.
Our first approach was to confirm this hypothesis by studying Ihh expression in cultured chondrocytes.
This approach was abandoned due to the extreme cytotoxicity of the dithiocarbamates. Since sterolization is an important
post-translational modification of hedgehog proteins, an inhibitor of cholesterol biosynthesis (a statin) was fed to young chicks
as a means of perturbing hedgehog activity. These chicks exhibited depressed growth rate and a TD-like lesion in the
prehypertrophic zone of the epiphyseal growth plate. Supplementary dietary cholesterol resulted in normal growth plate
morphology, although the growth rate depression was not reversed.
These results were exciting, but we were faced with a dilemma: which hedgehog is being inhibited?
Wu et al. (2002) have reported that both Ihh and Sonic Hedgehog (Shh) are expressed in the post-natal avian growth plate,
with Shh being expressed distal to Ihh. We have confirmed the presence of Shh in lysates of hypertrophic chondrocytes with
western blotting. The expression of two hedgehogs at different locations in the growth plate supports previous suggestions
that hedgehog proteins have dual actions in growth plate physiology.
Currently we are using immunohistochemistry, western blotting and microarray technology to identify the downstream targets
of hedgehog genes responsible for the impaired angiogenesis associated with the development of tibial dyschondroplasia.
Research authored by Dr. Leach
Click the tab and a window will appear.
List of Publications via PubMed
(NIH National Library of Medicine)
List of Publications via PubMed
(NIH National Library of Medicine)
| Dr. Leach's research |
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| ||||||||||
The MHE Research Foundation, we comply with the HONcode standard for health trust worthy information: By the Health On the Net Foundation. Click
here to verify.# HON Conduct 282463 and is linked on the NIH National Library of Medicine, Directory of Health Organizations (SIS) website, as well as
the link for Patient Information on The Diseases Database a cross-referenced index of human disease, and 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
here to verify.# HON Conduct 282463 and is linked on the NIH National Library of Medicine, Directory of Health Organizations (SIS) website, as well as
the link for Patient Information on The Diseases Database a cross-referenced index of human disease, and 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.
| This website is regularly reviewed by members of the Scientific and Medical Advisory Board of the MHE Research Foundation. All online submission forms use (SSL 3.0, RC4 with 128 bit encryption (High); RSA with 1024 bit exchange) Protocol with Privacy protection. Our goal is to make this website as safe and user friendly as possible. |
| The MHE Research Foundation is a participating member organization of the United States Bone and Joint Decade, (USBJD) & the USBJD Rare Disease Patient Network |
| Email the webmaster: webmaster@mheresearchfoundation.org Materials on this website are protected by copyright Copyright © 2009 The MHE Research Foundation |
| This web page was updated last on 6/21/09, 4:0O pm Eastern time |
| Written consent must be obtained to attach web pages or the files attached to this website. Please email webmaster. |
Disclaimer: While many find the information useful, it is in no way a substitute for professional medical care. The information provided here is for educational
and informational purposes only. This website does not engage in the practice of medicine. In all cases we recommend that you consult your own physician
regarding any course of treatment or medicine.
and informational purposes only. This website does not engage in the practice of medicine. In all cases we recommend that you consult your own physician
regarding any course of treatment or medicine.
The MHE Research Foundation is proud to be an affiliate of the Society For Glycobiology
