Gaucher Disease is a debilitating lysosomal storage disorder characterized by striking visceral enlargement and a high risk of crippling fractures. It s caused by mutations in the glucocerebrosidase (GBA1) gene that impair -glycosidase, an enzyme required for sphingolipid catabolism. While enzyme replacement therapy (imiglucerase) is effective, its effects on fracture risk are not fully understood. To identify new therapeutic targets for non-neuronopathic type 1 GD (GD1), attempts have been made to knock in mutations and delete Gba1 in mice. We have successfully deleted Gba1 in cells of the hematopoietic and mesenchymal cell lineage using an Mx1 promoter. Our Mx1-Cre:GD1 mouse phenocopies human GD1 almost in its entirety, displaying severe hepatosplenomegaly, cytopenia, and osteoporosis. The mouse also displays Th1 and Th2 hypercytokinemia and immune cell defects, which might contribute not only to the increased risk of lymphoproliferative malignancy, but also to the bone disease. Our data further show that the osteoporosis is due to a defect in osteoblastic bone formation, not osteoclastic bone resorption. We find that reduced osteoblast viability noted in stromal cell cultures from Mx1-Cre:GD1 mice is recapitulated by exposure to sphingosine, a sphingolipid that accumulates in GD1. We hypothesize that, despite the immune cell dysfunction that may affect bone, the osteopenia noted in Mx1-Cre:GD1 mice arises mainly from the direct action of sphingosine on the osteoblast, thus lowering bone formation. Therefore, in Specific Aim 1, we will determine whether the bone formation defect is autonomous, and if so, which bone cell - osteoblast, osteocyte, or osteoclast - drives it. For this we will delete Gba1 in the three cell types, respectively, using Col2.3-Cre, Dmp1-Cre and CathK-Cre mice.
In Specific Aim 2, we will lower sphingolipid levels by inhibiting or deleting glucosylceramide synthase (Gcs), an enzyme upstream of Gba1. For this, we will inject Mx1-Cre:GD1 mice with eliglustat tartrate, a Gcs inhibitor, and, in parallel, generate mice lacking Gba1 and Gcs in the same cells. Of note, we find that eliglustat tartrate lowers serum GL-1 and reverses the visceromegaly and cytopenia in GD1 patients. Finally, in Specific Aim 3, to hone in on the specific lipid that causes osteoblast inhibition, we will lower sphingosine, but not LysoGL-1 levels. We hypothesize that, as the extralysosomal enzyme Gba2 converts LysoGL-1 to sphingosine, Gba2 deletion or its inhibition by AMP-DNM should reverse the osteopenia in Mx1-Cre:GD1 mice. To further examine the action of sphingosine and other sphingolipids on the osteoblast, we will study differentiation, cell cycling and apoptosis in vitro. Our investigations should not only define the target cell and responsible molecule for the osteopenia in GD1, but also identify new therapeutic targets, both upstream (Gcs) and downstream (Gba2) of Gba1, for GD1-associated and other common types of osteoporosis.

Public Health Relevance

Gaucher Disease is a genetic disorder that has an incidence of up to 1 in 850 live births in the Ashkenazi Jewish population. Our groups at Mount Sinai and Yale School of Medicine have generated a mouse model that recapitulates all features of Gaucher Disease, including severe osteoporosis. This proposal will identify the molecular mechanisms underlying the osteoporosis by using a combination of genetically-modified mice and pharmacologic tools. Our studies should form the basis of new therapies for this crippling disease.

National Institute of Health (NIH)
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Research Project (R01)
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Special Emphasis Panel (ZRG1)
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Sharrock, William J
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Icahn School of Medicine at Mount Sinai
Internal Medicine/Medicine
Schools of Medicine
New York
United States
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