Glucocerebrosidase gene-deficient mouse recapitulates Gaucher disease displaying cellular and molecular dysregulation beyond the macrophage

Abstract

In nonneuronopathic type 1 Gaucher disease (GD1), mutations in the glucocerebrosidase gene (GBA1) gene result in glucocerebrosidase deficiency and the accumulation of its substrate, glucocerebroside (GL-1), in the lysosomes of mononuclear phagocytes. This prevailing macrophage-centric view, however, does not explain emerging aspects of the disease, including malignancy, autoimmune disease, Parkinson disease, and osteoporosis. We conditionally deleted the GBA1 gene in hematopoietic and mesenchymal cell lineages using an Mx1 promoter. Although this mouse fully recapitulated human GD1, cytokine measurements, microarray analysis, and cellular immunophenotyping together revealed widespread dysfunction not only of macrophages, but also of thymic T cells, dendritic cells, and osteoblasts. The severe osteoporosis was caused by a defect in osteoblastic bone formation arising from an inhibitory effect of the accumulated lipids LysoGL-1 and GL-1 on protein kinase C. This study provides direct evidence for the involvement in GD1 of multiple cell lineages, suggesting that cells other than macrophages may be worthwhile therapeutic targets.

Risk factors for fractures and avascular osteonecrosis in type 1 Gaucher disease: A study from the International Collaborative Gaucher Group (ICGG) Gaucher Registry

“…Given the role of osteoblast dysfunction in the development of osteopenia of GD1, (11,17,18) it will be important to determine whether alternative treatments with small molecule substrate reduction therapy, whose volume of distribution includes cells other than macrophages, result in an enhanced therapeutic effect. In a pooled retrospective study of GD1 patients, substrate reduction therapy with miglustat appeared to modestly increase bone mineral density.…”

“…(40) Interestingly, increased osteoblast apoptosis and resulting loss of vascular endothelial growth factordependent angiogenesis support has been implicated in humans and in animal models of AVN receiving glucocorticoids. (41)(42)(43) Osteoblastic dysfunction (17) and abnormalities of mesenchymal stem cells (44) have been described in animal models of GD and in a human patient, respectively. Both these cell types are essential components of the hematopoietic microenvironment, and dysfunction of either or both could conceivably link AVN and anemia as secondary phenomena.…”

“…(12,13) Although osteopenia in GD is commonly attributed to increased osteoclastic bone resorption, (14) it is more likely related to impaired osteoblast function (15,16) associated with accumulating lipids. (17,18) Importantly, it is not known whether osteopenia in GD1 increases the risk of fractures as it does in postmenopausal women. (19) Imiglucerase therapy improves bone mass and bone mineral density (12,13,(20)(21)(22)(23) and studies have shown an apparent decrease in reports of bone pain and bone crises.…”

Unexpected macrophage-independent dyserythropoiesis in Gaucher disease

“…21 Moreover, an important extramedullary hematopoiesis with the presence of erythroid cells was observed in the spleen of a murine model of GD. 9,10 We previously detected GCerase activity in normal erythroblasts but not in circulating RBCs. 11 High lipid levels have been frequently reported in the plasma and RBCs of GD patients, [22][23][24][25] which raises the possibility that the RBCs are overloaded with lipids due to the passive incorporation of GlcCer and/or that the erythroid progenitors are primarily affected.…”

“…However, a growing number of studies performed on murine and in vitro models as well as those using cells from GD patients, indicate that the pathophysiology of GD may involve a wider array of cell types, including hematopoietic and mesenchymal cells, thymic T cells and progenitors, dendritic cells and osteoblasts. [5][6][7][8][9][10] We have previously shown that the red blood cells (RBCs) of GD patients exhibit abnormal morphological, rheological and functional properties, and could be considered additional factors in the GD pathophysiology on the basis that they can trigger ischemic events. 11 Importantly, a study of a large cohort revealed that anemia was the only risk factor for avascular osteonecrosis, the most debilitating skeletal complication for GD type 1 patients.…”