Differential influence on bone remodeling by regulators of Wnt-dependent signal transduction

• Applicant: Professor Thorsten Schinke, Ph.D.
• Subject Area: Orthopaedics, Traumatology, Reconstructive Surgery ; Cell Biology
• Term: from 2013 to 2017
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 235869912

Since the discovery of activating and inactivating mutations of the gene LRP5 in individuals with osteosclerosis and osteoporosis, respectively, Wnt signaling is considered a major regulatory pathway in bone-forming osteoblasts. Indeed, Lrp5 has been described as a co-receptor for ligands of the Wnt family and as a molecular target for endogenous antagonists of Wnt signaling. Given the potential relevance of these findings in terms of an osteoanabolic treatment of skeletal disorders, it is a major goal of basic science to understand the complex interactions of Lrp5 at the cell surface and the thereby regulated intracellular events in osteoblasts at the molecular level. This is particularly true for the question, which specific ligands, receptors and antagonists of Wnt signaling are relevant for bone formation, since these molecules could alternatively be utilized as molecular targets for an osteoanabolic therapy.Based on our own preliminary work in this context we came to three important conclusions: 1) The Wnt receptor Fzd9 is a positive regulator of bone formation. 2) The transmembrane protein Krm2, which functions as a receptor of the Wnt antagonist Dkk1, is a negative regulator of bone formation that additionally activates osteoclastogenesis. 3) While Krm2 inhibits ß-catenin-dependent Wnt signaling, Fzd9-deficiency only affects so-called non-canonical Wnt signaling pathways. To further study these potentially relevant discrepancies, this project aims at the generation of genetically modified mouse models for histological and molecular analyses, thereby addressing at least three questions: 1) Is Fzd9 a physiologically relevant interaction partner of Lrp5? 2) Which molecular effects of Krm2 are mediated by an interaction with Lrp5? 3) Is the action of Sost, whose mutational inactivation causes osteosclerosis, mediated by Wnt signaling antagonism?

• DFG Programme: Research Grants