title: Osteocyte Alterations Induce Osteoclastogenesis in an In Vitro Model of Gaucher Disease.
abstract: Gaucher disease (GD) is caused by mutations in the glucosylceramidase β (GBA 1) 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, mainly in the monocyte/macrophage lineage. Its mildest form is Type I GD, characterized by non-neuronopathic involvement. Bone compromise is the most disabling aspect of the Gaucher disease. However, the pathophysiological aspects of skeletal alterations are not yet fully understood. The bone tissue homeostasis is maintained by a balance between resorption of old bone by osteoclasts and new bone formation by osteoblasts. A central player in this balance is the osteocyte as it controls both processes. We studied the involvement of osteocytes in an in vitro chemical model of Gaucher disease. The osteocyte cell line MLO-Y4 was exposed to conduritol-β-epoxide (CBE), an inhibitor of GCase, for a period of 7, 14 and 21 days. Conditioned media from CBE-treated osteocytes was found to induce osteoclast differentiation. GCase inhibition caused alterations in Cx43 expression and distribution pattern and an increase in osteocyte apoptosis. Osteoclast differentiation involved osteocyte apoptotic bodies, receptor activator of nuclear factor κ-B ligand (RANKL) and soluble factors. Thus, our results indicate that osteocytes may have a role to play in the bone pathophysiology of GD.
authors.affiliation: Instituto de Estudios Inmunológicos y Fisiopatológicos (IIFP), CONICET-UNLP, 1900 La Plata, Argentina. cmbondar@gmail.com.
authors.forename: Constanza
authors.initials: C
authors.lastname: Bondar
authors.affiliation: Instituto de Estudios Inmunológicos y Fisiopatológicos (IIFP), CONICET-UNLP, 1900 La Plata, Argentina. maxi.ormazabal@gmail.com.
authors.forename: Maximiliano
authors.initials: M
authors.lastname: Ormazabal
authors.affiliation: Instituto de Estudios Inmunológicos y Fisiopatológicos (IIFP), CONICET-UNLP, 1900 La Plata, Argentina. andrea.crivaro@gmail.com.
authors.forename: Andrea
authors.initials: A
authors.lastname: Crivaro
authors.affiliation: Instituto de Estudios Inmunológicos y Fisiopatológicos (IIFP), CONICET-UNLP, 1900 La Plata, Argentina. malenaferreyra@gmail.com.
authors.forename: Malena
authors.initials: M
authors.lastname: Ferreyra-Compagnucci
authors.affiliation: Instituto de Inmunología, Genética y Metabolismo (INIGEM), Hospital de Clínicas "José de San Martín", Facultad de Medicina, CONICET-Universidad de Buenos Aires, Paraguay 2155, C1121ABG Buenos Aires, Argentina. victuare@gmail.com.
authors.forename: María Victoria
authors.initials: MV
authors.lastname: Delpino
authors.affiliation: Instituto de Estudios Inmunológicos y Fisiopatológicos (IIFP), CONICET-UNLP, 1900 La Plata, Argentina. paularozenfeld@gmail.com.
authors.forename: Paula Adriana
authors.initials: PA
authors.lastname: Rozenfeld
authors.affiliation: Instituto de Estudios Inmunológicos y Fisiopatológicos (IIFP), CONICET-UNLP, 1900 La Plata, Argentina. juanmarcosmucci@gmail.com.
authors.forename: Juan Marcos
authors.initials: JM
authors.lastname: Mucci
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001854:Bone Marrow Cells / Q000473:pathology; D002454:Cell Differentiation / Q000187:drug effects; D002460:Cell Line; D018031:Connexin 43 / Q000378:metabolism; D017077:Culture Media, Conditioned / Q000494:pharmacology; D005260:Female; D005776:Gaucher Disease / Q000473:pathology*; D007294:Inositol / Q000031:analogs & derivatives / Q000494:pharmacology; D039641:Integrin beta Chains / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008810:Mice, Inbred C57BL; D008954:Models, Biological; D010010:Osteoclasts / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D010011:Osteocytes / Q000473:pathology*; D010012:Osteogenesis / Q000187:drug effects*; D053244:Osteoprotegerin / Q000378:metabolism; D053245:RANK Ligand / Q000494:pharmacology; D012995:Solubility
chemical_list: D018031:Connexin 43; D017077:Culture Media, Conditioned; D039641:Integrin beta Chains; D015850:Interleukin-6; D053244:Osteoprotegerin; D053245:RANK Ligand; D007294:Inositol; C011423:conduritol epoxide
keywords: Gaucher disease; apoptotic bodies; bone; osteoclast; osteocyte