Glucocerebrosidase deficiency in zebrafish leads to primary osteogenic defects.

Ostopenia and other skeletal complications have a considerable influence on the morbidity of patients affected by Gaucher disease (GD). Despite the development of novel therapeutic approaches, bone response to current enzymatic replacement is slow and bone manifestations may worsen or persist in affected patients. The pathogenetic mechanisms responsible for bone alterations are currently unknown. Aim: This study was aimed to analyze bone defects occurring in a fish model with a morpholino-induced glucocerebrosidase (GBA) deficiency. Moreover, key molecular pathways affected by GBA loss of function were investigated. Methods: We used a set of transgenic biosensor fish to identify the involvement of targeted cell signaling pathways as a consequence of GBA deficiency. Confocal live imaging on cartilage and bone specific trangenics and transcriptomic analysis were additionaly used to perform a detailed spatiotemporal characterization of key molecular genes affected by GBA loss of function. Results. Our study suggests that well-defined osteogenic defects occur during early life stages in fish larvae lacking correct glucocerebrosidase functional activity. Moreover, when testing a set of biosensor reporter fish, we found a specific impairment of signaling pathways, which are good candidates in bone formation. Discussion. An early onset of cell signaling alterations detected in our fish model supports a view that GBA loss of function leads to premature primary bone defects , which significantly compromise bone remodeling in later stages. This study emphasizes the use of an early therapeutic intervention in GD affected children and suggests potential novel key targets for therapy of the skeletal disorders in GD.