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


Osteoporose is een botziekte met een grote persoonlijke sociale last en drukt ook  op het gezondheidszorgbudget. Osteoporose wordt gekarakteriseerd door verlies van botmassa en daardoor botsterkte en een toename van de kans op botbreuken. Er bestaan medicijnen om verder botverlies tegen te gaan (afbraakremmers). De grote uitdaging is om therapieën te ontdekken waardoor bot dat verloren is gegaan hersteld wordt. Het onderzoek richtte zich op de botvormende cel, de osteoblast. In analogie met de ontwikkeling van een baby naar volwassenheid, ontwikkelt de botvormende cel zich vanuit een stamcel. De onderzoekers hebben dit proces bestudeerd en onderzocht hoe de botvormende activiteit versterkt kon worden. Vergelijkbaar met een zich ontwikkelend kind bleek de gevoeligheid voor externe prikkels (bijvoorbeeld hormonen) en de activiteit van de botvormende cel afhankelijk van het ontwikkelingsstadium. Het onderzoek heeft verschillende aangrijpingspunten voor nieuwe botvorming stimulerende therapieën opgeleverd. In een vervolgonderzoek worden deze  bestudeerd en de mogelijkheden om deze klinisch te gaan toepassen.

Titel: Systems biology towards life in silico: mathematics of the control of living cells
Auteur: Westerhoff HV, Kolodkin A, Conradie R, Wilkinson SJ,Bruggeman FJ, Krab K, van Schuppen JH, Hardin H, Bakker BM, Moné MJ, Rybakova KN, Eijken M, van Leeuwen HJ, Snoep JL
Magazine: Journal of Mathematical Biology
Titel: • What it takes to understand and cure a living system: computational systems biology and a systems biology-driven pharmacokinetics-pharmacodynamics platform
Auteur: Swat M, Kielbasa SM, Polak S, Olivier B, Bruggeman F, Tulloch MQ, Snoep JL, Westerhoff HV
Magazine: Interface Focus
Titel: • Noise management by molecular networks
Auteur: Bruggeman FJ, Blüthgen N, Westerhoff HV
Magazine: PLoS Computational Biology
Titel: GPM6B regulates osteoblast function and induction of mineralization by controlling cytoskeleton and matrix vesicle release.
Auteur: Drabek K, van de Peppel J, Eijken M, van Leeuwen JPTM
Magazine: Journal of Bone and Mineral Research
Titel: Opposing actions of rosiglitazone and resveratrol on mineralization in human vascular smooth muscle cells
Auteur: Bruedigam C, Eijken M, Koedam M, Chiba H, van Leeuwen JPTM
Magazine: Journal of Molecular and Cellular Cardiology
Titel: • Proteomic analysis of human osteoblastic cells: relevant proteins and functional categories for differentiation.
Auteur: Alves RD, Eijken M, Swagemakers S, Chiba H, Titulaer MK, Burgers PC, Luider TM, van Leeuwen JP
Magazine: Journal of Proteome Research
Titel: • Wnt signaling acts and is regulated in a human osteoblast differentiation dependent manner
Auteur: Eijken M, Meijer IM, Westbroek I, Koedam M, Chiba H, Uitterlinden AG, Pols HA, van Leeuwen JP
Magazine: Journal of Cellular Biochemistry
Titel: • Design principles of nuclear receptor signaling: how complex networking improves signal transduction
Auteur: Kolodkin AN, Bruggeman FJ, Plant N, Moné MJ, Bakker BM, Campbell MJ, van Leeuwen JP, Carlberg C, Snoep JL, Westerhoff HV
Magazine: Molecular Systems Biology
Titel: IFNbeta impairs extracellular matrix formation leading to inhibition of mineralization by effects in the early stage of human osteoblast differentiation.
Auteur: Woeckel VJ, Eijken M, van de Peppel J, Chiba H, van der Eerden BC, van Leeuwen JPTM.
Magazine: Journal of Cellular Physiology
Titel: Decreased oxygen tension lowers reactive oxygen species and apoptosis and inhibits osteoblast matrix mineralization through changes in early osteoblast differentiation.
Auteur: Nicolaije C, Koedam M, van Leeuwen JPTM
Magazine: Journal of Cellular Physiology
Titel: • 1Alpha,25-(OH)2D3 acts in the early phase of osteoblast differentiation to enhance mineralization via accelerated production of mature matrix vesicles
Auteur: Woeckel VJ, Alves RD, Swagemakers SM, Eijken M, Chiba H, van der Eerden BC, van Leeuwen JP
Magazine: Journal of Cellular Physiology
Titel: Evidence for multiple peroxisome proliferator-activated receptor gamma transcripts in bone: fine-tuning by hormonal regulation and mRNA stability
Auteur: Bruedigam C, Koedam M, Chiba H, Eijken M, van Leeuwen JP
Magazine: FEBS Letters
Titel: • A new concept underlying stem cell lineage skewing that explains the detrimental effects of thiazolidinediones on bone.
Auteur: Bruedigam C, Eijken M, Koedam M, van de Peppel J, Drabek K, Chiba H, van Leeuwen JP
Magazine: Stem Cells
Titel: The activin A-follistatin system: potent regulator of human extracellular matrix mineralization
Auteur: M Eijken, S Swagemakers, M Koedam, C Steenbergen, P Derkx, AG Uitterlinden, PJ van der Spek, JA Visser, FH de Jong, HA Pols, JPTM van Leeuwen
Magazine: FASEB Journal

Samenvatting van de aanvraag

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.

Onderdeel van programma:
Gerelateerde subsidieronde:
Projectleider en penvoerder:
Prof. dr. J.P.T.M. van Leeuwen
Verantwoordelijke organisatie:
Erasmus MC