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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
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List of Publications via PubMed
(NIH National Library of Medicine)
List of Publications via PubMed
(NIH National Library of Medicine)
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Dr. Leach's research
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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
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