Gaucher disease-associated alterations in mesenchymal stem cells reduce osteogenesis and favour adipogenesis processes with concomitant increased osteoclastogenesis

CRIVARO, A.; BONDAR, C.; MUCCI, J.; ORMAZABAL, M.; FELDMAN, ROBERTO; DELPINO, VICTORIA; ROZENFELD, P.

MOLECULAR GENETICS AND METABOLISM

ACADEMIC PRESS INC ELSEVIER SCIENCE

Lugar: Amsterdam; Año: 2020

1096-7192

Gaucher disease (GD) is caused bypathogenic mutations in GBA1, the gene that encodes the lysosomal enzyme β-glucocerebrosidase.Until now, treatments for GD cannot completely reverse bone problems. The aimof this work was to evaluate the potential of MSCs from GD patients (GD MSCs)to differentiate towards the osteoblast (GD Ob) and adipocyte (GD Ad) lineages,and their role in osteoclastogenesis. We observed that GD Ob exhibited reducedmineralization, collagen deposition and alkaline phosphatase activity (ALP), aswell as decreased gene expression of RUNX2, COLA1 and ALP. We also evaluatedthe process of osteoclastogenesis and observed that conditioned media from GDMSCs supernatants induced an increase in the number of osteoclasts. In thismodel, osteoclastogenesis was induced by RANKL and IL-1β. Furthermore, resultsshowed that in GD MSCs there was a promotion in NLRP3 and PPAR-γ geneexpression. Adipogenic differentiation revealed that GD Ad had an increase inPPAR-γ and a reduced RUNX2 gene expression, promoting adipocytedifferentiation. In conclusion, our results show that GD MSCs exhibiteddeficient GD Ob differentiation and increased adipogenesis. In addition, we showthat GD MSCs promoted increased osteoclastogenesis through RANKL and IL-1β.These changes in GD MSCs are likely to contribute to skeletal imbalanceobserved in GD patients