This application is designed to study the role of modulation of growth regulatory molecules in the process of endochondral ossification that takes place in the growth plates, and during bone development in the fetus. The regulatory processes of interest are those controlled by FGFR3 (fibroblast growth factor receptor 3) and PTHrPR (parathyroid hormone-related peptide receptor) expression on the chondrocyte, and by variations in the sulfation of the surrounding proteoglycans. Such molecules are known to influence growth plate organization in both human chondrodysplastic, and transgenic or knock-out mice. The planned work is based on the hypothesis that these regulatory molecules are functionally-related, with PTHrPR activation being able to stimulate proteoglycan sulfation, and proteoglycan sulfation being able to regulate FGFR3 activity, which in turn down-regulates endochondral bone growth.
Three Specific Aims will evaluate the interrelationships of the molecules.
In Specific Aim 1, the role(s) of FGFR3 in growth plate cartilage will be characterized by testing the effects of FGFs on chondrocytic development in bone explants;
in Aim 2, the interrelationship between the PTHrP and FGF systems will be addressed using appropriate genetic models;
Specific Aim 3 will explore the influence of matrix (proteoglycan) sulfation in the growth plate, particularly in relation to the PTHrP and FGF systems. The work will involve the use of transgenic or knock-out mice in which the receptors are either not expressed, or expressed in an active form, and in which proteoglycan sulfation is impaired. The work not only relates to the fundamental process of the control of endochondral ossification, but also to the mechanisms whereby loss of control may lead to a chondrodysplasia. It may also point to ways in which such loss of control can be overcome, and so could potentially indicate new treatment strategies.
| Aikawa, T; Segre, G V; Lee, K (2001) Fibroblast growth factor inhibits chondrocytic growth through induction of p21 and subsequent inactivation of cyclin E-Cdk2. J Biol Chem 276:29347-52 |
