Full Text Sources
Gaucher disease (GD) is an inherited disorder in which mutations in the GBA1 gene lead to deficient β-glucocerebrosidase activity and accumulation of its substrate glucosylceramide. Bone disease is present in around 84% of GD patients, ranging from bone loss including osteopenia and osteonecrosis to abnormal bone remodelling in the form of Erlenmeyer flask formation. The range of severity and variety of types of bone disease found in GD patients indicate the involvement of several mechanisms. Here we investigate the effects of exogenous sphingolipids on osteoclasts, osteoblasts, plasma cells and mesenchymal stem cells (MSC) and the interactions between these cell types. Osteoclasts were differentiated from the peripheral blood of Gaucher patients and control subjects. Osteoblasts were differentiated from mesenchymal stem cells isolated from bone marrow aspirates of Gaucher patients and control subjects. The human osteoblast cell line SaOS-2 was also investigated. Osteoclasts, osteoblasts and a human myeloma plasma cell line NCI-H929 were cultured with relevant exogenous sphingolipids to assess effects on cellular viability and function. Calcium deposition by osteoblasts differentiated from Gaucher patient MSC's was on average only 11.4% of that deposited by control subject osteoblasts. Culture with glucosylsphingosine reduced control subject MSC viability by 10.4%, SaOS-2 viability by 17.4% and plasma cell number by 40%. Culture with glucosylceramide decreased calcium deposition by control MSC-derived osteoblasts while increasing control subject osteoclast generation by 55.6%, Gaucher patient osteoclast generation by 37.6% and plasma cell numbers by up to 29.7%. Excessive osteoclast number and activity and reduced osteoblast activity may have the overall effect of an uncoupling between osteoclasts and osteoblasts in the GD bone microenvironment.
PMID: 29934064 [PubMed - as supplied by publisher]