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Start date: Mar 1, 2012, End date: Feb 29, 2016 PROJECT  FINISHED 

Bone is a dynamic tissue that is constantly remodelled by the coupled activities of matrix-producing osteoblasts (OBs) and matrix-resorbing osteoclasts (OCs). Uncoupled bone remodelling may lead to low bone mass, causing osteoporosis and ultimately fractures, which constitute an increasing medical- and socio-economic problem. During fracture repair, a functional relationship exists between migrating OBs and the invading vasculature. To better understand physiological and disturbed bone remodelling, bone repair, and the communication between bone and vessels, it is crucially important to investigate molecular mechanisms regulating OB function, OB motility, and the bone-vascular niche. Resulting insights can then be used to improve the current cure of osteoporosis and fracture repair. Preliminary data revealed that the homeodomain protein Tg-interacting factor (Tgif) is an important regulator of OB function. Tgif-deletion in mice causes a low bone mass with spontaneous fractures, a disturbed bone marrow vascular network, and a compromised fracture healing with a reduced OB migration. Furthermore, Tgif-deficiency reduces the expression of the angiogenic factor Vegf-A by OBs and Tgif physically interacts with the cell motility regulator focal adhesion kinase (FAK), suggesting molecular mechanisms for the role of Tgif in vivo. Thus, the objectives of this proposal are to analyze the function of Tgif (i) in OB motility and FAK signalling, and (ii) in the regulation of Vegf-A expression and the bone-vascular niche. Both objectives will be accomplished using a state-of-the-art genetic approach in mice for the targeted deletion of Tgif in OBs and a complete set of complementary in vitro assays. Taken together, this project will establish Tgif as a novel physiological regulator of OB motility and the bone-vascular niche, thus reporting clinically important knowledge to improve the treatment of low bone mass diseases and fractures.

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