Projet ANR-08-GENO-0009 – Dros : Implication des gènes du développement Dlx5 et Runx2 dans le déterminisme de l¿ostéoporose corticale
Programme : Du gène à la physiopathologie, des maladies rares aux maladies communes (GENOPAT) 2008
Année de financement : 2008
Coordinateur du projet : INSTITUT NATIONAL DE LA SANTE ET DE LA RECHERCHE MEDICALE - ADR PARIS VII - ADR 12 (INSTITUT NATIONAL DE LA SANTE ET DE LA RECHERCHE MEDICALE - ADR PARIS VII - ADR 12)
Partenaires : Centre national de la recherche scientifique; Institut national de la santé et de la recherche médicale
Montant : 360000.0 euros
Durée : 36 mois
Résumé : The development of new approaches to treat osteoporosis represents a major clinical need. There was a tremendous increase over the last two decades in the fundamental understanding of the mechanisms regulating bone remodeling with the final aim to develop new anabolic therapies for bone disorders (Khosla et al, 2008). Cortical bone is a major determinant of bone strength. The mechanisms of bone remodeling are likely to be different in cancellous and in cortical bone which is distant from the red marrow that contains the osteoprogenitors. Although the basic mechanisms of bone remodeling are suppose to be similar in both compartments, the molecular mechanisms of bone loss, i.e. osteoblast-osteoclast crosstalk, are very likely to be different in the two compartments. The genes regulating the early phase of bone development also affected the acquisition of the peak bone mass and thereby the process of bone loss. The effect of gender in bone indicates also site specificity (Seeman et al, 20 There is a major gender difference in changes of cortical bone with age: men lose less bone than women from the endosteal envelope and they gain more on the periosteal envelope. 
Because the involvement of developmental genes are crucial for building bones and are known to act on  bone modelling but also remodeling during growth as well as ageing, their role in the pathogenesis of osteoporosis needs to be better defined. Our proposal is intended to advance our understanding of the sequential genetic events involving two genes Dlx5 and Runx2. These genes are known to be crucial for normal skeletal development and bone mass acquisition but their genetic defects also affect cortical bone differently in males and females. We proposed also here to determine the existence of a significant gene-gene and gene-environment interaction in the determination of cortical BMD in male and females that involves DLX5 and one isoforme of RUNX2 gene, and to identify possible upstream regulators and downstream effectors. Our findings in both mice and humans may provide novel insights to treat osteoporosis related to ageing.
 We expect that the physiopathological knowledge we will gain about the interaction between dlx5 and runx2 in controlling cortical bone structure will help designing new target for osteoporosis treatment in the future. The upstream regulators and downstream effectors that this project also aimed at identifying, will also open new field of research in the pathophysiology of osteoporosis.The studies described in this proposal are also intended to lead to the discovery of several potential genes that regulate bone remodeling and coupling between formation and resorption. This information could be commercially valuable, and result in the development of intellectual property rights. The strategic impact of the project will be to identify a series of molecules and signalling pathways that can potentially used for the design of new drugs.