Deficiency of thyroid hormone in children results in delayed skeletal maturation, disorganization of the cartilage columns of the growth plates, and impaired differentiation of growth plate chondrocytes into hypertrophic cells. These abnormalities are often clinically manifested as severe growth retardation and mechanical failure of the growth plates of the hips (slipped capital femoral epiphyses). Despite exciting advances in the understanding of how systemic hormones and peptide growth factors regulate growth and differentiation in a number of target tissues, the molecular mechanisms by which thyroid hormone exerts these profound effects on bone growth and development have remained an enigma. Evidence is accumulating to suggest that systemic hormones and peptide growth factors in general, and thyroid hormone in particular, may regulate cell growth and differentiation, in part through control of the cell cycle. A chemically-defined model of growth plate chondrocyte differentiation has been developed which is not only exquisitely sensitive to thyroid hormone, but also results in morphogenesis of chondrocytes into a columnar pattern similar to the in vivo growth plate. This model will be used to determine if thyroid hormone regulates the transition between chondrocyte growth and differentiation, in part through inhibiting progression of cells through the cell cycle.
The Specific Aims of this project are: 1) to define the role of thyroid hormone in regulating the transition from cell growth to cell differentiation in this chemically-defined model of growth plate chondrocyte differentiation; 2) to characterize the cell cycle response to thyroid hormone-induced terminal differentiation in this system; and 3) to overexpress specific cell cycle proteins in growth plate chondrocytes, by transient transfection, to determine their effect on thyroid hormone signalling.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
First Independent Research Support & Transition (FIRST) Awards (R29)
Project #
5R29AR044880-04
Application #
6349958
Study Section
Orthopedics and Musculoskeletal Study Section (ORTH)
Program Officer
Grave, Gilman D
Project Start
1998-02-01
Project End
2002-01-31
Budget Start
2001-02-01
Budget End
2002-01-31
Support Year
4
Fiscal Year
2001
Total Cost
$121,184
Indirect Cost
Name
Case Western Reserve University
Department
Orthopedics
Type
Schools of Medicine
DUNS #
077758407
City
Cleveland
State
OH
Country
United States
Zip Code
44106