title: Proinflammatory and proosteoclastogenic potential of peripheral blood mononuclear cells from Gaucher patients: Implication for bone pathology.
abstract: Gaucher disease (GD) is caused by mutations in the GBA gene that confer a deficient level of activity of glucocerebrosidase (GCase). This deficiency leads to the accumulation of the glycolipid glucocerebroside in the lysosomes of cells of monocyte/macrophage system. Bone compromise in Gaucher disease patients is the most disabling aspect of the disease. However, pathophysiological aspects of skeletal alterations are still poorly understood. On the other hand it is well known that inflammation is a key player in GD pathology. In this work, we revealed increased levels of the proinflammatory CD14(+)CD16(+) monocyte subset and increased inflammatory cytokine production by monocytes and T cells in the circulation of GD patients. We showed increased levels of osteoclast precursors in PBMC from patients and a higher expression of RANKL in the surface of T cells. PBMC from patients presented higher osteoclast differentiation compared to healthy controls when cultured in the presence of M-CSF alone or in combination with RANKL. In vitro treatment with Velaglucerase reduced osteoclast levels to control levels. On the other hand THP-1 derived osteoclast precursors cultured in the presence of conditioned media from PBMC of GD patients presented higher differentiation to active osteoclasts. This induction involved TNF-α and RANKL.
authors.affiliation: IIFP, Departamento de Ciencias Biológicas, Facultad de Ciencias Exactas, Universidad Nacional de La Plata - CONICET, La Plata 1900, Argentina.
authors.forename: J M
authors.initials: JM
authors.lastname: Mucci
authors.affiliation: Servicio de Hematología, Hospital de Niños "Sor María Ludovica", La Plata, Argentina.
authors.forename: M F
authors.initials: MF
authors.lastname: Cuello
authors.affiliation: Sanatorio Urquiza, Quilmes, Argentina.
authors.forename: I
authors.initials: I
authors.lastname: Kisinovsky
authors.affiliation: Consultorio Larrea N° 1106 3°E, Buenos Aires, Argentina.
authors.forename: M
authors.initials: M
authors.lastname: Larroude
authors.affiliation: Instituto de Inmunología, Genética y Metabolismo (INIGEM), Hospital de Clínicas "José de San Martín", Facultad de Medicina, Universidad de Buenos Aires, Buenos Aires, Argentina.
authors.forename: M V
authors.initials: MV
authors.lastname: Delpino
authors.affiliation: IIFP, Departamento de Ciencias Biológicas, Facultad de Ciencias Exactas, Universidad Nacional de La Plata - CONICET, La Plata 1900, Argentina. Electronic address: paurozen@biol.unlp.edu.ar.
authors.forename: P A
authors.initials: PA
authors.lastname: Rozenfeld
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000954:Antigens, Surface; D001862:Bone Resorption; D001842:Bone and Bones / Q000378:metabolism / Q000473:pathology; D002454:Cell Differentiation; D002648:Child; D016207:Cytokines / Q000378:metabolism; D005260:Female; D005776:Gaucher Disease / Q000175:diagnosis / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D006801:Humans; D016130:Immunophenotyping; D018836:Inflammation Mediators / Q000378:metabolism; D007963:Leukocytes, Mononuclear / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D010010:Osteoclasts / Q000166:cytology / Q000378:metabolism*; D055815:Young Adult
chemical_list: D000954:Antigens, Surface; D016207:Cytokines; D018836:Inflammation Mediators
keywords: Bone pathology; Gaucher disease; Glucocerebrosidase deficiency; Osteoclasts; Osteoimmunology