CORDIS - EU research results

Molecular mechanisms of bone homeostasis

Final Report Summary - OSTEOGENE (Molecular mechanisms of bone homeostasis)

Osteoporosis (OP) is a metabolic bone disease characterised by loss of bone mass and disturbed bone architecture compromising bone strength and thereby predisposing for fractures. OP is today a major health problem of increasing concern in the European Community, the USA and in Asia. OP behaves as a 'silent epidemic' until the first fracture occurs because the disease is recognised too late and grossly under-diagnosed in Western countries.

Primary OP shows a strong gender bias in which the genetic predisposition is important. At least 4 out of 10 women after 50 years of age will sustain at least one fracture because of OP during their lifetime, while 1 out of 5 men will experience a similar fracture. Secondary OP, e.g. due to metabolic diseases or medical treatments, is also a prevalent disease in the European Community. The mechanisms behind and the etiology of primary OP are unknown, but somehow the dynamic processes of bone remodelling that comprise bone homeostasis have failed.

The OSTEOGENE project had as a major objective to study and characterise the molecular mechanisms causing or leading to OP and to create substantial evidence based knowledge for early diagnosis, prevention and improved treatment of the disease.

The project objectives consisted of scientific achievements and development and implementation of novel technology in addition to defined management tasks. The basis and foundation of this work represented the inclusion of patients and healthy subjects who had been clinically expert evaluated in relation to post-menopausal OP in women and male OP, including a cohort of patients with secondary form of metabolic OP due to primary hyperparathyroidism. In addition, recruitment of young and adolescent healthy males represented an important task for genetic studies.

Biobank containing blood and tissue samples was established, functional genetics studies were complemented and extended with genetic linkage analyses in informative families. Genetic loci of importance for determination of bone mineral density, which is about 80 % genetically dependent, were studied in healthy males of different age groups. A major objective was the study of the molecular mechanisms underlying primary OP in women.

The results achieved in OSTEOGENE fulfilled all the listed objectives. For the first time a 'molecular disease map' was created for important forms of OP in humans. These results take the project beyond the state of the art not only in terms of advancement of the knowledge base, but also because of its impact on front line research and industry. Thus, the work uncovered novel disease related gene products which lent themselves to commercial exploitation.

The original idea, which turned out to be successful, was to examine osteoporotic trabecular bone as the site of manifest illness in comparison to healthy control bone and to analyse the data using state-of-the-art bioinformatics and statistics based on generated gene expression profiles. From these lists showing the differentially expressed transcripts between sick and healthy bone, OP candidate gene products were selected and tested in cell culture- and transgene animal models.