Efficacy of an anti-inflammatory treatment in in-vitro model of Gaucher Disease

ORMAZABAL, MAXIMILIANO E.; BONDAR, CONSTANZA M.; ROZENFELD, PAULA A.; CRIVARO, ANDREA N.; CECI, ROMINA; MUCCI, JUAN M.; SIMONARO, CALOGERA

Clermont-Ferrand

Congreso; 13th European Working Group on Gaucher Disease; 2019

European Working Group on Gaucher Disease

Gaucher?s disease (GD), the most common lysosomal storage disorder, is caused by mutations in the gene GBA1 encoding for the lysosomal enzyme glucocerebrosidase. Glucocerebrosidase deficiency leads to the accumulation of the substrates glucosylceramide and glucosphingosine. This abnormalities in lysosomal function can cause an induction of the inflammatory pathways. The existence of chronic stimulation of the immune system is a hallmark in many lysosomal disorders, characterized by high levels of proinflammatory cytokines. Beyond the fact that the role of inflammation in the pathology of GD is poorly understood, the idea of an adjunctive therapy that targets inflammation may be a suitable option for patients. A compound called pentosan polysulphate (PPS) that have anti-inflammatory effects have been proposed in mucopolysaccharidoses. So, we hypothesized that PPS could be a useful adjunctive therapy to inflammation for Gaucher. The objective of this work is to analyze the in vitro effect of PPS on inflammatory cytokines in cellular models of GD, and to study its effect in GD associated in vitro bone alterations.Cultures of peripheral blood mononuclear cells (PBMCs) from Gaucher patients were exposed to PPS and evaluated the proinflammatory cytokines production. PPS treatment significantly reduced levels of this cytokines. Moreover, this treated PBMCs have a reduced tendency to differentiate to osteoclasts. Respect to a GD in vitro bone cells model, we used osteoblasts and osteocytes cell lines incubated with an inhibitor of glucocerebrosidase (CBE) in the presence or absence of PPS. The conditioned media was harvested in order to analyze if those cells secrete factors that induce osteoclastogenesis. Conditioned media from this cell cultures exposed to PPS produced lower numbers of osteoclasts. Taken together, we could demonstrate that PPS is an effective molecule to reduce the production of proinflammatory cytokines in in vitro models GD and it was effective at ameliorating bone alterations of in vitro models of GD. Our results suggest that PPS should be considered as a potential adjunctive therapy for Gauche Disease, moreover, it was effective at ameliorating bone alterations of in vitro models of Gaucher disease