Exploration of the mouse osteoblast transcriptome

Abstract

Contains fulltext : 30023.pdf (publisher's version ) (Open Access)The frequently occurring bone disorder osteoporosis is characterized by a strong increase in bone fracture risk, caused by a dramatically disturbed balance in the activity of the cells that degrade bone (osteoclasts) and cells that synthesize new bone (osteoblasts). Therapies against osteoporosis are currently based on inhibition of osteoclast activity in order to reduce the amount of bone resorption. An alternative strategy would be to stimulate new bone formation by enhancing the activity of osteoblasts. The main objective of this thesis was to identify genes of which expression and function are specifically associated with the differentiation of mesenchymal stem cells into osteoblasts. Therefore, we used microarray-based gene expression profiling to study the transcriptome of differentiating osteoblasts during in vitro cell culture as well as in their physiological context during skeletogenesis. The analyses revealed many genes of which expression in osteoblasts had not previously been detected. Novel markers of osteoblast differentiation and bone development were identified as well as putative in vivo target genes of the transcription factor Runx2 which is a key regulator of skeletal development. One of the markers identified encodes the protein Wif1 (Wnt Inhibitory Factor 1), which was shown to be specifically expressed in osteoblasts during embryonic development. Typically, genes encoding antagonists of the Wnt signalling pathway were strongly expressed during late stages of osteoblast differentiation and implicate an important role of Wnt antagonism in the maturation of osteoblasts. Given the role of Wnt signalling in the maintenance of bone mass, this class of proteins may be potential drug targets to treat bone disorders. This thesis shows that the combination of microarray technology and bioinformatic analyses has provided new possibilities to the understanding of bone biology. Consequently, our studies have contributed to a more detailed knowledge on osteoblast differentiation and provide focus points to develop strategies that will prevent and treat bone disorders.Radboud University, Applied Biology, 4 juni 2007Promotores : Olijve, W., Zoelen, E.J.J. van Co-promotor : Dechering, K.J.264 p