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New genes and targets for osteoporosis


As the proportion of the elderly population is increasing in Europe, the frequency of osteoporosis fractures is also expected to increase unless appropriate preventive measures are implemented. The costs associated with osteoporosis-related fractures in Europe are estimated to be 10,000 million EURO annually. It has been established that among the risk factors of osteoporosis there is an important genetic component; the specific genes involved are just beginning to be identified. We intend to gather an in-depth knowledge of the genes involved in the pathogenesis of this disease, to elucidate their mutual interactions and understand how to regulate their expression pharmacologically. We will then use this knowledge to develop new diagnostic, preventive and therapeutic approaches.
As it is evident from the detailed report attached most of the objectives of GENOSPORA have been largely attained, the main problem encountered was that tartranates did not prove a sufficiently interesting target to be developed into a product. This has led the industrial partner Dompe to leave the Consortium as it could not reach its aims. The role of main industrial partner has now been taken by Aventis Pharma which is going, through its spinout Proskelia, to assure the technology transfer of thee results of our consortium towards application. The major achievements have been: Objective 1 was completely fulfilled. We have set up the screening methods to find new mutation affecting bone phenotype. A total of 7 lines with defective bone formation have been established by Partner 6 (GSF) one of them, BCC/ENU5 shows osteopetrosis in the homozygous mutant at 16/30 weeks. Partner 7 (Ingenium) set up a high-throuput assay to analyse mutant animals for dominant and recessive defects in bone formation. This screen could analyze up to 100 different mutant animals per day. Out of about 4500 lines analysed and of 150 pedigrees, 7 dominant lines were identifyied and the underlying mutation was mapped by positional cloning.

A new candidate gene Phex was identified as two of the dominant mutations affected this same gene. 45 recessive lines with aberration in different parameters were identified. These studies are continuing as osteoporosis is a defect associated with ageing and it might be necessary to analyze old animals. Objective 2 was over-fulfilled, we analysed the regulatory region of Krox-20, and we are identifying a new transcription factor critical for the control of bone homeostasis. Mice mutant for Dlx5 and Dlx5/Dlx6 have been generated and have been analysed for their bone phenotype. Mice with the mutation of Dlx6 are in a very advance stage of production. Krox-20 conditional mutants have been generated. Cbfa1 conditional mutant mice have been generated. This part of the projects proceeded very well thanks to the coordinated contribution of several of the partners. The mice obtained are still going to be studied in the next years during the ANABONOS consortium with support from EU. Objective 3 was fulfilled. The different forms of ER in bone were studied both in osteoblasts and in osteoclasts. Specific ER promotors have been identified for osteoblasts and osteoclasts. We now know the mechanisms regulating specificallt ER expression in the bone compartment and new strategies to define drugs affecting ER expression in bone can be designed. The most important and innovative observation regards the diffence in isoforms of ER present in osteoblasts and osteoclasts.

The differential expression of ER-__protein isoforms and their distinct functional impact in different tissues indicates that future chemotherapeutic strategies should take into account the influence that different ER_ isoforms can have in estrogen-mediated physiological and pathological processes. Objective 4 was fulfilled. We collected DNA sample from a large population of osteoporotic patients (see details in the report) and we set up the screen for new mutation of the RUNX2/CBFA1 gene and for KROX-20 in the osteoporotic populations. We could actually identify new mutations both in the RUNX2/CBFA1 and KROX20 gene associated with an osteoporotic phenotype. This collection of DNA will be available for new screens on the new genes identified in by Objective 1. This is a typical example of interaction between basic science and medical research to generate practical results. Objective 5 was fulfilled. New diagnostic tools have been developed by Partner 4. These are essentially monoclonal antibodies directed against osteocalcin and C-telopeptide. An assay for human cathepsin K was completed with the generation of monoclonal antibodies and the design of an assay. These same antibodies might prove also of interest for therapeutic applications. Objective 6 is ongoing, we hope that one of the outcomes of ANABONOS will be to fulfil this objective. The study of tartranates proved somehow unsatisfactory and this led the industrial Partner 5 to exit the Consortium as it had lost interest in the development of this specific class of drugs. Aventis Pahrma/Proskelia took its place and is now actively collaborating with members of the consortium to develop new therapeutic approaches t osteoporosis.

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