The impact of selenium and selenoproteins on stem cell based bone regeneration and regulation of celcium metabolism

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Monocytes terminally differentiate into a variety of tissue macrophages (MP), dendritic cells (DC) and osteoclasts (OC). Key regulators of differentiation are nuclear receptors for retinoic acid and vitamin D3, kinase-mediated signal transduction by LPS, adhesion, (G)MCSF and TNF-related signaling systems like TRANCE/RANK. The latter involves NFkB activation and is essential for OC and DC differentiation and function. NFkB activity is modulated by the selenoenzyme thioredoxin reductase a (TrxRa). Selenoproteins are a group of enzymes which functionally depend on the incorporation of selenocysteine mediated by a 3'- regulatory hairpin structure of the respective mRNA. The selenoenzymes glutathione peroxidases (GPx) and TrxR are expressed in macrophages. Activation of macrophages is accompanied by an oxidative burst, mediated by the enzyme complex NADPH oxidase. This project sets out to elucidate the contribution of GPxs and TrxRs to I) compartimentalization of the oxidative burst during phagocytosis, II) NFkB-mediated signal transduction for differentiation and reactivity of MP and DC using inducible TrxR overexpression and knockout and III) the modulation of differentiation, phagocytosis and infection through TrxR overexpression and knockout and its putative relevance in infection, autoimmunity and metabolic bone diseases.