Publications by authors named "Sebastian P van der Woning"

Background: Patients suffering from osteoporosis show an increased number of adipocytes in their bone marrow, concomitant with a reduction in the pool of human mesenchymal stem cells (hMSCs) that are able to differentiate into osteoblasts, thus leading to suppressed osteogenesis.

Methods: In order to be able to interfere with this process, we have investigated in-vitro culture conditions whereby adipogenic differentiation of hMSCs is impaired and osteogenic differentiation is promoted. By means of gene expression microarray analysis, we have investigated genes which are potential targets for prevention of fat cell differentiation.

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S-adenosylmethionine (SAM)-dependent methylation of biological molecules including DNA and proteins is rapidly being uncovered as a critical mechanism for regulation of cellular processes. We investigated the effects of reduced SAM-dependent methylation on osteoblast differentiation by using periodate oxidized adenosine (ADOX), an inhibitor of SAM-dependent methyltransferases. The capacity of this agent to modulate osteoblast differentiation was analyzed under non-osteogenic control conditions and during growth factor-induced differentiation and compared with the effect of inhibition of DNA methylation by 5-Aza-2'-deoxycytidine (5-Aza-CdR).

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The epidermal growth factor (EGF)-like growth factors bind their ErbB receptors in a highly selective manner. Recently, we have shown that the sequence YYDLL in the C-terminal linear region is compatible with binding to all ligand-binding ErbB receptors. In the present study, we show that introduction of the YYDLL sequence into the ErbB1 specific ligands EGF and transforming growth factor-alpha (TGFalpha) broadened their receptor specificity towards ErbB4.

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ErbB3 transactivation can make tumor cells resistance to ErbB1/ErbB2 targeting drugs. This urges for a reliable method to determine cell surface ErbB3 levels, but in our hands iodinated NRG1beta is unstable and tends to underestimate the number of ErbB3 receptors in a radio-receptor assay. Here we show by the use of a radio-labeled high affinity neuregulin mutant NRG/YYDLL that ErbB3 levels can be determined in a reliable manner by Scatchard analysis.

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Epidermal growth factor (EGF)-like growth factors bind their ErbB receptors in a highly selective manner, but the molecular basis for this specificity is poorly understood. We have previously shown that certain residues in human EGF (Ser(2)-Asp(3)) and TGFalpha (Glu(26)) are not essential for their binding to ErbB1 but prevent binding to ErbB3 and ErbB4. In the present study, we have used a phage display approach to affinity-optimize the C-terminal linear region of EGF-like growth factors for binding to each ErbB receptor and thereby shown that Arg(45) in EGF impairs binding to both ErbB3 and ErbB4.

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The family of epidermal growth factor (EGF)-like ligands binds to ErbB receptors in a highly selective manner. Previous studies indicated that both linear regions of the ligand play a major role in determining receptor selectivity, and phage display studies showed that each region could be optimized independently for enhanced affinity. In this study, we broadened the ErbB binding specificity of EGF by introducing the optimal sequence requirements for ErbB3 binding in both the N- and C-terminal linear regions.

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EGF-like growth factors activate their ErbB receptors by promoting receptor-mediated homodimerization or, alternatively, by the formation of heterodimers with the orphan ErbB-2 through an as yet unknown mechanism. To investigate the selectivity in dimer formation by ligands, we have applied the phage display approach to obtain ligands with modified C-terminal residues that discriminate between ErbB-2 and ErbB-3 as dimerization partners. We used the epidermal growth factor/transforming growth factor alpha chimera T1E as the template molecule because it binds to ErbB-3 homodimers with low affinity and to ErbB-2/ErbB-3 heterodimers with high affinity.

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