Gaucher hMSCs present an altered osteoblast and adipose differentiation

BONDAR, CONSTANZA; DELPINO, VICTORIA; MUCCI, JUAN MARCOS; ROZENFELD, PAULA; CRIVARO, ANDREA; ORMAZABAL, MAXIMILIANO

Congreso; Reunion conjunta SAIC SAI SAFIS; 2018

Gaucher disease (GD) is caused by mutations on the gene encodingthe lysosomal enzyme glucocerebrosidase. Type I GD (GD1) patientspresent diverse symptoms as chronic inflammation, anemia,hepatosplenomegaly and bone alterations. The most widespreadtreatment for GD, enzyme replacement therapy (ERT), cannot completelyreverse bone problems. Despite mechanisms leading to bonedamage are not fully described, reports suggest that alterations inosteoblasts and osteoclast, as well as a chronic pro-inflammatorystate, could be involved. It is known that mesenchymal stem cells(MSCs) differentiate to osteoblasts and adipocytes, so the aim ofthis work was to evaluate, in an in vitro model, the potential of MSCsfrom control and GD patients to differentiate towards the osteoblast(GDOb) and adipocyte (GDAd) lineage. Furthermore, we sought toanalyze released cytokines from differentiated osteoblasts and thecapacity of these cells to generate osteoclasts. The expression ofdifferentiation markers were lower in GDOb at 14 days compared tocontrol Ob: BMP-2 (p=0,001), Runx2 (p=0,01), ALP (p<0.0001) andColA1 (p<0.0001). Reduced mineralization, collagen deposition andalkaline phosphatase activity were revealed (all p<0.0001). We alsoobserved that GD MSCs supernatants promoted osteoclastogenesis(p=0,04) and presented higher levels of IL-1β (p=0,004). However,we did not observe any difference in TNF-α concentration. GDMSCs produced lower levels of lipid droplets than control MSCs at7 (p=0,001) and 14 (p<0.0001) days of adipose differentiation. Ourresults show an alteration in GD MSC differentiation towards osteoblastand adipose lineage as well as an increased osteoclast differentiationcapacity and an altered cytokine secretion. Therefore, wesuggest that impairment in GD MSCs and its subsequent cytokineprofile could contribute to bone damage in GD.