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Erasmus Medical Centre

Principal Investigators: Professor Hans van Leeuwen and Dr Marc Raaijmakers

The groups led by Hans Van Leeuwen and Marc Raaijmakers collaborate closely in studies on the cross talk and modes of communication between the osteoblasts/bone microenvironment and HSC. The Van Leeuwen group aims to develop better diagnostics and therapies for skeletal disorders and disturbances in calcium homeostasis by a combination of molecular, cellular, animal, epidemiological and eventually clinical studies. This encompasses integrated lines of research focussing on:

· Characterisation of molecular mechanisms of bone cell differentiation and of bone formation and degradation using human bone cell models and bioinformatic and systems biological tools A) to identify and reconstruct transcription networks that determine osteogenic or adipogenic lineage differentiation, and B) to identify lineage specific markers for selecting and tracing of cell fate; C) to analyse by in vitro and in vivo approaches means to stimulate bone formation.

· Identification of risk determinants and drug targets for osteoporosis and osteoarthritis by genomics and proteomics approaches in combination with genetic epidemiological approaches within a.o. the Rotterdam Study;

· Calcium homeostasis and skeletal metabolism in relation to ageing by analyses of experimental animal models, e.g. premature ageing mice, as well as human population research.

Human MSC and osteoblast differentiation play an important role in the research in relation to bone formation and the interaction with osteoclasts and metastasizing tumor cells. Recent studies with human MSC and osteoblastic cell models have identified the importance of vitamin D signalling, activin/follistatin signaling, the impact of PPAR signaling and reactive oxygen species for MSC differentiation, osteoblast survival and bone extracellular matrix formation and mineralization. Extensive gene and protein profiling studies of human osteogenic MSCs and osteoblasts identified novel osteogenic specific transcription and protein profiles, demonstrated the significance of the cytoskeleton for proper osteoblast differentiation and extracellular matrix mineralization and substantiated the importance of the extracellular protein matrix produced by the osteoblasts for cell differentiation. Current attempts are to develop mathematical approaches for description of MSC and osteoblast behaviour in (heterogeneous) cell populations. Prof. van Leeuwen has long term international collaborations with Prof. Hewison, Dept Orthopedics; Prof. van Wijnen and Stein and Lian, Dept. Cell Biology, Univ. Massachusetss, USA on various aspects of bone cell biology. Also with Prof. R. Smith (Scripps Research Institute Florida) and Y. Sun (Huffington Center on Ageing, Houston) on the ghrelin action in bone. The group participated in the projects GEFOS (FP6), NucSys (FP6 Marie Curie RTN) and GENOMOS (FP7, coordinating organisation).

The Raaijmakers group is interested in the role of the bone marrow microenvironment in hematopoiesis and diseases of the hematopoietic system, particularly the initiation and evolution of pre-leukemic bone marrow disorders, such as bone marrow failure and myelodysplastic syndromes. The studies aim to elucidate how specific cellular elements and molecular pathways within the bone marrow microenvironment contribute to disease pathogenesis and tumorigenesis in these conditions. The laboratory strives to translate findings in pre-clinical models to human disease and explore therapeutic modalities aimed at targeting the bone marrow niche. The work of the Raaijmakers group aims to 1.reveal the molecular changes on the transcriptome and proteomic level in osteolineage cells in genetic mouse models with preleukemic hematopoietic disease. 2. Characterize concomitant alteration of endothelial and hematopoietic cells, the extracellular matrix and systemic effects. 3. Model the crosstalk of these compartments in the disruption of hematopoiesis in culture systems and genetic mouse models. 4. Elucidate molecular determinants governing the effects on hematopoiesis and test their relevance for human disease. Dr Raaijmakers collaborates with the Erasmus Stem Cell Institute and the Center for Regenerative Medicine, Harvard Stem Cell Institute, U.S.A.

1. Alves RD, Eijken M, Swagemakers S, Chiba H, Titulaer MK, Burgers PC, Luider TM, van Leeuwen JP Proteomic analysis of human osteoblastic cells: relevant proteins and functional categories for differentiation. J Proteome Res. 2010 Sep 3;9(9):4688-700.

2. Bruedigam C, Eijken M, Koedam M, van de Peppel J, Drabek K, Chiba H, van Leeuwen JP. A new concept underlying stem cell lineage skewing that explains the detrimental effects of thiazolidinediones on bone. Stem Cells. 2010 May;28(5):916-27.

3. Eijken M, Swagemakers S, Koedam M, Steenbergen C, Derkx P, Uitterlinden AG, van der Spek PJ, Visser JA, de Jong FH, Pols HA, van Leeuwen JP. The activin A-follistatin system: potent regulator of human extracellular matrix mineralization. FASEB J. 2007 Sep;21(11):2949-60.

4. MHGP Raaijmakers. Niche contribution to oncogenesis: evolving concepts and implications for the hematopoietic system. Haematologica 2011, in press

5. MHGP Raaijmakers, S. Mukherjee, S.Guo, T. Kobayashi, S. Zhang, J. Schoonmaker, B. Ebert, C. Lin, J. Rommens, DT Scadden. Osteoprogenitor cell dysfunction induces myelodysplasia and secondary leukemia. Nature. 2010 Mar 21

Click here to view latest publications of Hans van Leeuwen in PubMed

Click here to view latest publications of Marc Raaijmakers in PubMed