Uncoupling of osteoblast-osteoclast regulation in a chemical murine model of Gaucher disease.
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 accumulation of the glycolipid glucocerebroside in the lysosomes of cells of monocyte/macrophage system. Type I GD is the mildest form and is characterized by the absence of neuronopathic affection. Bone compromise in Gaucher disease patients is the most disabling aspect of the disease. However, pathophysiological aspects of skeletal alterations are still poorly understood. The homeostasis of bone tissue is maintained by the balanced processes of bone resorption by osteoclasts and formation by osteoblasts. We decided to test whether bone resorption and/or bone formation could be altered by the use of a chemical in vitro murine model of Gaucher disease. We used two sources of cells from monocyte/macrophages lineage isolated from normal mice, splenocytes (S) and peritoneal macrophages (PM), and were exposed to CBE, the inhibitor of GCase (S-CBE and PM-CBE, respectively). Addition of both conditioned media (CM) from S-CBE and PM-CBE induced the differentiation of osteoclasts precursors from bone marrow to mature and functional osteoclasts. TNF-α could be one of the factors responsible for this effect. On the other hand, addition of CM to an osteoblast cell culture resulted in a reduction in expression of alkaline phosphatase and mineralization process. In conclusion, these results suggest implication of changes in both bone formation and bone resorption and are consistent with the idea that both sides of the homeostatic balance are affected in GD.
LISIN, Departamento de Ciencias Biológicas, Facultad de Ciencias Exactas, Universidad Nacional de La Plata, La Plata 1900, Argentina.
Juan M
JM
Mucci
Florencia
F
Suqueli García
Pablo N
PN
de Francesco
Romina
R
Ceci
S
S
Di Genaro
Carlos A
CA
Fossati
M Victoria
MV
Delpino
Paula A
PA
Rozenfeld
D000818:Animals; D000943:Antigens, Differentiation / Q000378:metabolism; D001854:Bone Marrow Cells / Q000502:physiology; D002113:Calcification, Physiologic; D002454:Cell Differentiation; D002478:Cells, Cultured; D017077:Culture Media, Conditioned; D005776:Gaucher Disease / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology*; D007294:Inositol / Q000031:analogs & derivatives; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010006:Osteoblasts / Q000378:metabolism*; D010010:Osteoclasts / Q000502:physiology*; D010014:Osteolysis / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000502:physiology
D000943:Antigens, Differentiation; D017077:Culture Media, Conditioned; D014409:Tumor Necrosis Factor-alpha; D007294:Inositol; C011423:conduritol epoxide
ARS; Alizarin Red S; Bone disease; CBE; CM; Conditioned media; Conduritol-beta-epoxide; GBA; GCase; GD; Gaucher disease; Glucocerebrosidase deficiency; Knock out mice for cell surface receptor of TNF-α; M-CSF; MC3T3; MMP; Macrophages; Matrix metalloproteinases; Murine osteoblasts cell line; PM; Pathophysiology; RANKL; Receptor activator of nuclear factor kappa-B ligand; S; SDS; Splenocytes; TNF-α; TNFRKO; TNFRp55; TRAP; cell surface receptor of TNF-α; glucocerebrosidase; glucocerebrosidase gene; macrophage colony stimulating factor; peritoneal macrophages; sodium dodecyl sulfate; tartrate-resistant acid phosphatase; tumor necrosis factor alpha; α-MEM; α-minimum essential medium