Tracking Osteoblast Biodiversity : from a cognitive approach to preclinical trials for cell therapy of bone defects

Informations

Funding country

France

Acronym

OSTEODIVERSITY

URL

-

Start date

10/1/2012

End date

10/1/2015

Budget

541,934 EUR

Fundings

Abstract

Bone pathophysiology reveals a differential behaviour of jaw and long bones. This is illustrated by a recent Public Health concern: jaw osteonecrosis induced by anti-resorptive agents that are otherwise extremely efficient on long bones against osteoporosis and in oncology. Impaired long-term maintenance of grafts from long bones into the jaw is a second illustration of clinical unsolved questions. While early morphogenesis of the different parts of the skeleton has been investigated in detail, the mechanisms regulating site-specific post-natal bone physiology have not been fully assessed. This project is focused on the osteoblasts. Indeed, these mesenchymal cells exert directly a central role in bone matrix production and biomineralization, and control indirectly local bone resorption. Our hypothesis is that an autonomous specificity of the osteoblast phenotypes exists and is related to their embryological origins. Firstly, osteoblasts derive from neural crests for jaws and mesoderm for long bones. Secondly, their anatomical patterning depends on distinct homeobox-containing genes (Hox clusters for the axial and appendicular skeleton and divergent homeogenes such as Msx2 for the cranio-facial area). And finally, preliminary findings show that jaw osteoblasts overexpress a set of proteins which were previously considered to be enamel-specific. A comparative transcriptomic study has been conducted on the jaw vs. tibial bone in collaboration with a Norwegian group specialized in bioinformatics and genomics. Three differentially expressed enamel proteins (held from this study) will be analyzed on jaw/tibia osteoblasts. Due to technical limitations inherent to the mineralized nature of bone matrix, a set of approaches which are innovative to the consortium will enable to track the three enamel proteins in bones. The neurectodermal or mesodermal origin of osteoblasts will also be traced using lineage-specific promoters. Isolation of neurectodermal osteoblasts will allow deciphering the relationships between the embryological origin, the anatomical site and the differential phenotype. These will be explored at the molecular level as well as their functional consequences in vitro and in vivo using homotopic and ectopic graftings. Human gingival progenitor cells will be used for bone grafts as a human model of neurectodermic cells able to repair bone. These preclinical experiments would constitute the basis of cell therapy in humans. To analyze the cell-autonomous impact of Msx2, which would play a role in the site-specific phenotype of the osteoblasts, an Msx2 null mutation will be targeted in the osteoblasts. A multiscale analysis, from molecules to 3D-anatomy, will be conducted on the entire skeleton of these transgenic mice. The expected results will identify signaling pathways (Msx2/enamel proteins, their partners and targets) underlying physiopathological site-specificity which could be analyzed in depth thanks to the new models developed here. This pluridisciplinary project federates three teams dedicated to oral sciences, bone physiopathology and developmental biology. The data will generate new tools in bone loss diagnosis and treatment. The biomedical market is important. Osteoporosis is a major cause of fractures, invalidity, long term-hospitalization and morbidity. In the oral cavity, a functional handicap is very frequent due to an important number of different oral pathologies generating bone loss. These require complex rehabilitation which is painful, expensive, repetitive and increased by aging.