Endocrinology 1

Bone and Mineral Research

Principal Investigators

Prof.Dr S.E. Papapoulos, Dr N.A.T. Hamdy, Dr G. van der Pluijm, Prof.Dr C.W.G.M. Löwik

Aim and focus

Diseases of the skeleton are very common and cause significant morbidity and mortality. Examples include osteoporosis, bone metastases from breast and prostate cancer and Paget’s disease of bone. The pathogenesis of skeletal diseases is still not completely understood and despite advances in therapeutics, new treatment modalities are needed. The long-term goal of this research programme is the development of improved methods for diagnosis, prevention and treatment of bone diseases based on understanding of the molecular mechanisms responsible for normal and pathological bone metabolism using cellular, animal and human models.

Current research focus includes the study of:

• molecular mechanisms of mesenchymal stem cell differentiation into bone and cartilage cells, a  fundamental process for the development and maintenance of skeletal integrity;
• mechanisms responsible for the development of overt bone metastases from micrometastases in the bone marrow from breast and prostate cancer and their treatment;
• the role of angiogenesis in normal bone development, fracture healing and bone metastases;
• the control of bone formation by osteoblasts and its regulation by the Wnt-signalling pathway with specific focus on sclerostin, an osteocyte specific negative regulator of bone formation;
• the pathophysiology of secondary osteoporoses; the molecular basis of Paget’s disease of bone;
• the long-term effects of bisphosphonates in juvenile, idiopathic, postmenopausal and secondary osteoporosis.

Position in international context

Specific areas of the programme are amongst internationally recognized cutting-edge research, as also evidenced by the participation of the group in four FP6 and two FP7 projects funded by the European Union and its function as a platform for technology and training in molecular imaging techniques in Europe with special focus, within the LUMC network, on small animal optical imaging and high magnetic field MRI. Furthermore, the group holds an international leading position in the research on the basic and clinical pharmacology of the bisphosphonates, the most commonly used pharmacological intervention in patients with bone diseases.

Content/highlights/achievements

• The application of 2D and 3D whole body imaging of gene expression and cellular and molecular processes involved in bone formation and bone metastasis.
• The identification of the molecular mechanism of action of bisphosphonates and the description of their clinical pharmacokinetics in osteoporosis, Paget’s disease of bone and metastatic bone disease.
• The elucidation of the mechanism of action of sclerostin.
• The application for the first time in Europe of optical imaging technology to assess tumour development,  progression and bone metastasis in mice.
• The determination of genotypic-phenotypic relationships in familial Paget’s diseases of bone.

Future themes

• Further development and implementation of molecular imaging technology and of tools for functional pharmacogenomics and proteomic studies in stem cell differentiation and metastatic bone disease from breast and prostate cancer.
• Characterization and functional significance of genes, identified by cDNA array technology, in stem cell differentiation and tumour progression.
• Emphasis on translational research using patients with rare bone diseases (e.g. sclerosteosis van Buchem disease and High Bone Mass phenotype) to define the functional role of osteocytes and its secreted protein sclerostin on bone strength.
• The interactions of BMPs, sclerostin and wnt-signalling in the regulation of bone formation and the development of bone forming interventions for osteoporosis.
• The functional significance of mutated genes identified in patients with Paget’s disease of bone and the immunological basis of bone loss in COPD and IBD.

Cohesion within the LUMC

Apart from its structural (Urology, Pediatrics and Molecular Cell Biology) and thematic collaboration with several other clinical and non-clinical Departments, the programme is well embedded in major research themes of the LUMC such as angiogenesis, molecular imaging, regenerative medicine and stem cell research.

Key Publications

Papapoulos SE, Cremers SCLM. Prolonged bisphosphonate release after treatment in children. New England Journal of Medicine  2007; 356: 1075-76.
IF 51.3

Buis JT, Hendriquez NV, van Overveld PGM, van der Horst G, Que I, Schwaninger R, Rentsch C, ten Dijke P, Cleton-Jansen A-M, Driouch K, Ledereau R, Bachelier R, Vikicevic S, Clezardin P, Papapoulos SE, Cecchini M, Lowik CWGM, van der Pluijm G. Bone morphogenetic protein 7 in the development and treatment of bone metastases from breast cancer. Cancer Research 2007; 67: 8742-51.
IF 7.7

van Bezooijen R, Svensson PJ, Eefting D, Visser A, van der Horst G, Karperien M, Quax P, Vriendeling H, Papapoulos SE, ten Dijke P, Lowik CW. Wnt but not BMP signaling is involved in the inhibitory action of sclerostin on BMP-stimulated bone formation. Journal Bone and Mineral Research 2007; 22: 19-28.
IF 6.6

Kaijzel EL, van der Pluijm G, Löwik CW. Whole-body optical imaging in animal models to assess cancer development and progression. Clinical Cancer Research. 2007; 13: 3490-7.
IF 6.6

van der Pluim G, Que I, Sijmons B, Buijs JT, Lowik CWGM, Wetterwald A, Thalmann GN, Papapoulos SE, Cecchini MG. Interference with the microenvironmental support impairs the de novo formation of bonemetastases in vivo. Cancer Research 2005; 65: 7682-90.
IF 7.7

van Bezooijen RL, ten Dijke P, Papapoulos SE, Lowick CWGM. SOST\sclerostin, an osteocyte-derived negative regulator of bone formation. Cytokine & Growth Factor Reviews 2005; 16: 319-327.
IF 11.5

van Bezooijen RL, Roelen BAJ, Visser A, van der Wee-Pals L, de Wilt E, Karperien M Hamersma H, Papapoulos SE, ten Dijke P, Lowik CWGM. Sclerostin is an osteocyte-expressed negative regulator of bone formation, but not a classical BMP antagonist. Journal of Experimental Medicine 2004; 199: 805-814.
IF 14.5

Eekhoff EWM, Karperien M, Houtsma D, Zwinderman AH, Dragoiescu C, Kneppers ALJ, Papapoulos SE. Familial Paget’s disease in the Netherlands: occurrence, identification of new mutations in the sequestosome 1 gene and their clinical association. Arthritis and Rheumatism 2004; 50: 1650-1654.
IF 7.8

van der Eerden BCJ, Karperien M, Wit JM. Systemic and local regulation of the growth plate. Endocrine Reviews 2003; 24: 782-801.
IF 23.9

Ciana P, Raviscioni M, Mussi P, Vegeto E, Que I, Parker MG, Lowik C, Maggi A. In vivo imaging of transcriptionally active estrogen receptors. Nature Medicine 2003; 9: 805-11.
IF 28.6