Gaucher disease mesenchymal stem cells showed reduced osteogenesis and increased osteoclastogenesis and adipogenesis

ROZENFELD PA; CRIVARO, A.; BONDAR, C.; MUCCI JM; ORMAZABAL, M.; FELDMAN RA; DELPINO MV

Simposio; Lysosomal Disease Network-16th Annual WORLD Symposium; 2021

Introduction: Gaucher disease (GD) is caused by pathogenic variations in GBA1, the gene that encodes the lysosomal enzyme β-glucocerebrosidase. Until now, treatments for GD cannot completely reverse bone problems. The aim of 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. Results: We observed that GD Ob exhibited reduced mineralization, collagen deposition and alkaline phosphatase activity (ALP), as well as decreased gene expression of RUNX2, COLA1 and ALP. We also evaluated the process of osteoclastogenesis and observed that conditioned media from GD MSCs supernatants induced an increase in the number of osteoclasts. In this model, osteoclastogenesis was induced by RANKL and IL-1β. Furthermore, results showed that in GD MSCs there was a promotion in NLRP3 and PPAR-γ gene expression. Adipogenic differentiation revealed that GD Ad had an increase in PPAR-γ and a reduced RUNX2 gene expression, promoting adipocyte differentiation. Conclusion: our results show that GD MSCs exhibited deficient GD Ob differentiation and increased adipogenesis. We show that GD MSCs promoted increased osteoclastogenesis through RANKL and IL-1β. These changes in GD MSCs are likely to contribute to skeletal imbalance observed in GD patients.