- Geförderte Personen
Natur- und Biowissenschaften, Medizin
Developmental and pathological biomineralization - an essential role for ENPP 1
01.01.2012 - 01.01.2015
As a consequence of disease, injury or aging, ectopic mineralizations can occur in almost every tissue of the human body, and Diabetes mellitus and chronic kidney disease are the most prominent conditions associated with ectopic mineralizations. In any of the pathologies mentioned aberrant extracellular mineral levels play a role. Cardiovascular tissues are particularly prone to ectopic mineralization, the clinical consequences of which are stiffening of the blood vessels and altered hemodynamics leading to increased mortality due to cardiovascular failure. In a forward genetic screen we have isolated dragonfish as a zebrafish mutant showing a broad range of ectopic mineralizations. Mutant embryos not only display fused vertebrae but also show ectopic mineralization around perichondral bone, in the craniofacial skeleton, as well as, remarkably, in the brain, the neural tube and the heart. Using positional cloning and sequencing we could identify a premature stop-codon in the zebrafish orthologue of ENPP1 as the cause of this phenotype. ENPP1 is associated with the rare but very severe autosomal recessive disease idiopathic infantile arterial calcification (IIAC). ENPP1 has been described as a key regulator of extracellular pyrophosphate levels in mouse and human by metabolizing extracellular triphosphonucleotides to supply pyrophosphate, a well-known inhibitor of hydroxyappatite formation and a central factor in regulating biomineralization. However, beyond the mere regulation of pyrophosphate, some degree of cellular plasticity is involved in (pathological) biomineralization, e.g. through expression of osteo-/chondroblast specific genes in differentiated previously non-osteogenic cells. In my project, I aim to obtain a better understanding of biomineralization by studying the role of Enpp1 in zebrafish. A careful analysis of the Enpp1 phenotype with a particular focus on the aspects of ectopic mineralizations in the brain and in the heart will be conducted. Importantly, we have a number of transgenic lines available that allow, for the first time, in vivo observation of osteoblasts and osteoclasts in the context of ectopic mineralization. This unique opportunity to follow cell behavior with single cell resolution in wildtype and mutant contexts will shed new light on developmental osteogenesis as well as pathological mineralization.