A backbone to systems biology and multifactorial disease: systems biology of mineralization, bone formation and osteoporosis.

Common diseases are multi-factorial and have a complex aetiology. This is increasingly attributed to the fact that a multitude of interacting cellular processes control normal physiology and that faltering molecular networks rather than faulty individual factors are the basis of multifactorial disease. An integrative view of the processes and networks involved is crucial for a full understanding and improvement of diagnostics, risk prediction as well as therapy. This has been hampered in particular due to technical limitations and lack of cellular and analytical models while analyses were mostly restricted to single genes/proteins. The revolutionary progress in tools and techniques for genomic/proteomic analyses now allows full molecular dissection of multi-factorial diseases and to generate an integrative view. The clinical focus of this project is osteoporosis. Osteoporosis is a common age-related complex skeletal disease with a high personal, social and health economic burden. Osteoporosis is characterized by a decrease in bone quality as shown by a decrease in bone mineral density and by a structural deterioration of bone tissue with a consequent increase in bone fragility and fractures. Osteoblasts play a pivotal role in maintaining bone quality as they are the bone forming cells but also the directors of bone resorption by osteoclasts. Deranged osteoblast function is therefore a major etiological factor in osteoporosis and identifying the dominant genes/proteins involved will be of scientific, diagnostic and therapeutic importance. However, so far the proteins identified were often structural while only a few being regulatory, and moreover an integrated view of regulatory networks is still lacking. The HYPOTHESES OF THE CURRENT PROJECT is that characterizing genes and networks that regulate osteoblast differentiation and function and implementing this in a systems biology approach will: - identify regulatory networks that control osteoblast differentiation, bone formation and mineralization - deliver targets for understanding deranged osteoblast function leading to understanding development of osteoporosis - generate novel diagnostic, prognostic and therapeutic tools Following this hypothesis THE AIMS OF THE CURRENT PROJECT are: - generate an integrative systems biology view of the control of osteoblast differentiation and mineralization. - provide a first case study of a research program that employs systems biology to relate molecular networks to patients. This builds on our earlier: - development of a highly phenotypically characterized human osteoblast bone formation model - genome-wide gene expression analyses in relation to bone formation and mineralization - bioinformatics of these transcriptome data - systems biology of signal transduction networks - development of computer replicas of intracellular networks Based on this knowledge the current project will extend the global gene expression with protein expression profiling by nano-LC/mass spectrometry-based proteomic means and with functional characterization of genes in the networks identified, as well as with accurate determination of the time dependencies of signal transduction. The results will be interpreted, against the backdrop of all the available literature (mined by the bioinformatics component) by the use of the new Systems Biology type bottom-up models of the systems, which will start from the already available signal transduction model (e.g. www.siliconcell.net and/or http://receptorkinase.gsc.riken.jp). These approaches will deliver knowledge on the networks in control of osteoblast differentiation and function. Hierarchical analyses of the genes and proteins in these networks will provide a clear rationale to prioritize genes/proteins to be selected for genetic epidemiological and clinical studies. In a final phase of the project part of this will be proven by genetic association studies on osteoporosis (bone mineral density and fractures) in the Rotterdam Study. In conclusion, the project is a novel Systems Biology based approach to unravel complex diseases. It will provide an integrative view of control of osteoblast differentiation, bone formation / mineralization leading to a better understanding of deranged osteoblast function in the aetiology of osteoporosis and identification of diagnostic and therapeutic targets. It will also constitute one of the first cases were through Systems Biology failures in the networking of molecules are related to human pathophysiology.