Detailed project information

Title :  Longitudinal skeletal growth is influenced by the Vitamin-D3 hormone system through the PTHrP-Indian Hedgehog signaling loop.
Applicant : Dr. M.A. Tryfonidou - van Megen
Research institute : Universiteit Utrecht
Faculteit Diergeneeskunde
Departement Geneeskunde van Gezelschapsdieren
Team members : Dr. M.A. Tryfonidou - van Megen
Location : no information available
Duration : 02/01/2008 tot 01/31/2012
Strategic goal : Talent
Budget : Eur 176,443.00 personnel
Eur 24,000.00 equipment
Subsidy :  More Women Researchers as University Lecturers (MEERVOUD)
 
Summary
Longitudinal bone growth occurs at the growth plate. The growth plate contains one cell type (the chondrocyte) at different stages of differentiation: resting, proliferative and (pre)hypertrophic. The vitamin-D3 (VitD3) ? parathyroid hormone (PTH) axis plays a important endocrine role in calcium homeostasis and is essential for skeletal development. Additionally, these endocrine regulators contribute to local processes in the growth plate through the local VitD3-pathway and the PTH-related peptide (PTHrP)-Indian Hedgehog (IHH) growth-restraining loop.

Evidence from literature and findings from previous studies by the candidate lead to the overall hypothesis that the VitD3-pathway and the PTHrP-IHH loop interact with each other at the growth plate.

In vitro studies in primary chondrocytes cultures from vitD3-deficient reporter mouse strain harboring a Collagen 2-GFP transgene (Col2-pd2GFP) will allow a rational approach examining the overall hypothesis. Primary murine Col2-pd2GFP chondrocytes (isolated by FACS) will be challenged with VitD3-metabolites and silenced for one of the following gene products: 1a-hydroxylase, 24-hydroxylase, PTHrP, or IHH. In a stepwise approach the following specific hypothesis will be proven:

- 1,25(OH)2D3 regulates proliferative chondrocytes and their differentiation to hypertrophic chondrocytes mediated by the PTHrP-IHH loop.

- The PTHrP-IHH loop in turn influences the proliferative chondrocyte sensitivity to 1,25(OH)2D3.

The specific effect of 1,25(OH)2D3 on growth plate architecture and its interplay with the PTHrP-IHH growth restraining loop will be studied with the aid of comparative in vivo studies (VitD3 deficient vs. control Col2-pd2GFP mice).

The proposed project is an integral part of the main core research program ?Tissue Repair? within Utrecht University and the Academic Biomedical Center (ABC). New insight on the regulation of longitudinal growth is fundamental for the development of new preventive and therapeutic strategies for growth disorders.