Investigation of the role of the nuclear receptor NR4a1 during bone turnover and maintenance of the hematopoietic niche in the bone marrow

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Both metabolic and inflammatory disorders are accompanied by aggravated osteoporosis, which is characterized by a shifted balance between bone formation and bone resorption. Osteoclasts are key cellular players in the pathogenesis of osteoporosis since they mediate the process of increased bone resorption. Nuclear receptors are central regulators of fat and glucose metabolism. Moreover, they have been implicated in the modulation of the inflammatory response. Preliminary data of our groups show high expression of the nuclear receptor NR4A1 in cells of the monocytic lineage including macrophages and osteoclasts. Moreover these data indicate a dual role of this transcription factor both as regulator of bone metabolism and of inflammation. It is the aim of this project to further elucidate the role of NR4A1 in bone metabolism and inflammation in vivo and in vitro. We will study NR4A -/- mice and apply experimental models of postmenopausal osteoporosis (ovariectomy model), inflammatory osteoporosis (TNFα-transgenic mice) and mouse models of arthritis (TNFα- transgenic mouse model and K/BxN serum transfer). Using molecular approaches we will seek to identify target genes of the NR4A family of proteins and characterize their function in key cells such as macrophages, osteoclasts and osteoblasts. These experiments will help to understand the role of the NR4A family of nuclear receptors during chronic inflammatory disorders such as rheumatoid arthritis (RA) and during associated changes in bone metabolism, which will eventually lead to the identification of novel therapeutic targets for the treatment of these diseases.