Untersuchung der osteoimmunologischen Rolle von Dickkopf-1 bei Arthritis und Glukokortikoid-induzierter Osteoporose

• Antragstellerinnen / Antragsteller: Professor Dr. Lorenz C. Hofbauer; Professorin Dr. Martina Rauner
• Fachliche Zuordnung: Rheumatologie
• Förderung: Förderung von 2010 bis 2017
• Projektkennung: Deutsche Forschungsgemeinschaft (DFG) - Projektnummer 168825475

Glucocorticoids (GCs) are effective drugs in the treatment of inflammatory diseases, including various forms of arthritis. However, their use is limited by negative effects on bone mass and strength, resulting in increased osteoporotic fractures. GCs have adverse effects on bone cells, as they enhance osteoblast and osteocyte apoptosis and stimulate the receptor activator of NF-κB ligand (RANKL)/osteoprotegerin (OPG) ratio, translating into enhanced osteoclastogenesis. We recently demonstrated that RANKL blockade with a monoclonal antibody (denosumab) prevented loss of bone mass and strength that followed the administration of the glucocorticoid prednisolone. While this study demonstrated that targeting RANKL can prevent glucocorticoid-induced osteoporosis (GIO), the mechanistic details of how the glucocorticoid receptor (GR) mediates its therapeutic and skeletal side effects are still unclear. Recently, selective GR agonists (SEGRA) have been developed that favour transrepression of genes (required for therapeutic efficacy) over transactivation of genes (causing side effects). In this project, we plan to characterize the ability of novel SEGRAs to suppress inflammation while sparing the skeleton in vitro and in vivo, and to analyze the underlying mechanisms. Using murine GIO and arthritis models, we will assess the anti-inflammatory efficacy and pro-osteoporotic potential of these SEGRAs and compare them to prednisolone. Moreover, the interactions of SEGRAs with the RANKL/OPG system and Wnt signaling antagonists will be assessed. Detailed knowledge of the molecular mechanisms of GR signaling in bone and immune cells may help to identify GCs with an improved skeletal profile which may benefit patients affected by inflammatory disorders.

• DFG-Verfahren: Schwerpunktprogramme
• Teilprojekt zu: SPP 1468: Osteoimmunology - IMMUNOBONE - A Program to Unravel the Mutual Interactions between the Immune System and Bone
• Beteiligte Institution: Technische Universität Dresden ; Medizinische Fakultät Carl Gustav Carus ; Institut für Immunologie; Universität Ulm ; Fakultät für Naturwissenschaften ; Institut für Molekulare Endokrinologie der Tiere; Technische Universität Dresden ; Medizinische Fakultät Carl Gustav Carus ; Institut für Physiologische Chemie; Universität zu Lübeck ; Sektion Medizin ; Institut für Systemische Entzündungsforschung; Universitätsklinikum Erlangen AöR; Medizinische Klinik 3 - Rheumatologie und Immunologie; Internistisches Zentrum (INZ)