There is a gap in the field of growth research. There is a large body of work on growth on the whole body level in humans. There is also a large and rapidly growing body of work on growth-plate regulation in animals. There is little data, however, on growth- plate regulation in humans. We propose to bridge this gap. Linear growth is the result of the lengthening of the long bones of the skeleton; a process that occurs within the epiphyseal growth-plates. The regulation of longitudinal growth on the cellular level remains poorly understood, due to the difficulty of studying growth-plate chondrocytes in vitro. Recently, new techniques have been described that now permit us to study these cells. We will study human cells to answer basic questions about the hormonal regulation of the growth-plate and hence, linear growth. Growth-plate chondrocytes undergo two distinct phases of growth; a proliferative phase and a differentiation or """"""""hyper-trophic"""""""" phase. These phases are closely linked and must be tightly regulated. This project has the following specific aims: A) to outline the effects of known growth-regulating factors on human chondrocyte proliferation and differentiation and B) to identify possible regulatory pathways intrinsic to the growth-plate.
These aims will be met by testing four hypotheses. 1) GH directly increases expression and production of IGF-I in human growth- plate chondrocytes. 2) IGF-I is the primary stimulatory factor for human growth-plate chondrocyte proliferation. 3) Other factors, independent of GH and IGF-I, enhance growth-plate chondrocyte hypertrophy and differentiation. 4) IGF-I's effect is modulated by a factor(s) produced by hypertrophic chondrocytes, creating a negative feedback loop linking the two phases of chondrocyte growth. These hypotheses will be tested using chondrocytes from human growth-plates obtained at the time of epiphysiodesis. The cells will be fractionated by discontinuous Percoll gradients and cultured in alginate gel beads. Proliferation will be evaluated by [3H] thymidine uptake; differentiation by collagen type X expression and alkaline phosphatase production. A variety of known and suspected growth factors will be added to the cells to determine their role in growth-plate regulation. We propose to take what is known about animal growth-plate regulation and determine its relevance and importance in the human growth-plate, and to expand our knowledge of growth regulation in general. By identifying how these hormones alter the regulation in the growth-plate, we should be able to identify factors that can counteract them when their deficiency or excess causes growth-failure. These may represent future therapies for the treatment of growth failure. In addition, clinical genetics is identifying the mutations that result in osteochondrodyplasias. We will be in a position to study the role these genes play in growth-plate regulation and possibly identify therapeutic options. Conversely, by identifying the important regulators of the human growth-plate, we will provide clues to direct the search for the genes responsible for some of the osteochondrodysplasias.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Project (R01)
Project #
5R01AR045298-02
Application #
6171836
Study Section
Human Embryology and Development Subcommittee 1 (HED)
Program Officer
Sharrock, William J
Project Start
1999-09-28
Project End
2003-08-31
Budget Start
2000-09-01
Budget End
2001-08-31
Support Year
2
Fiscal Year
2000
Total Cost
$176,351
Indirect Cost
Name
Nemours Children's Clinic
Department
Type
DUNS #
City
Jacksonville
State
FL
Country
United States
Zip Code
32207