An excess of sphingolipids — a hallmark of Gaucher disease — contributes to an imbalance in bone formation and degradation, leading to the development of bone disease, according to researchers.
Their study, “Impact of sphingolipids on osteoblast and osteoclast activity in Gaucher disease,” was published in the journal Molecular Genetics and Metabolism.
Gaucher disease (GD) is a genetic disorder caused by mutations in the GBA1 gene, which leads to a deficiency in the activity of the β-glucocerebrosidase (GC) enzyme.
The GC enzyme is responsible for breaking down and recycling sphingolipids, a type of lipid, or fat, found in all mammalian cells. Gaucher patients have characteristic high levels of a sphingolipid called glucosylceramide in their cells and certain organs.
The most common form of Gaucher disease — type 1 GD — makes up about 94 percent of the Gaucher patient population. One of the most common features of these patients includes bone disease, which is present in about 84 percent of Gaucher patients.
Bone disease in GD patients can manifest in a number of ways, such as osteopenia (a condition where bone mineral density is lower than normal); osteonecrosis (a condition that occurs when there is loss of blood to the bone); osteosclerosis (abnormal hardening of bone and an increase in bone density); osteolytic lesions (areas of severe bone loss); pathological fracture; and abnormal bone remodeling.
The range of severity and types of bone disease suggest there are several mechanisms leading to bone disease in Gaucher patients.
Sphingolipids have been shown to regulate the activity and function of osteoclasts (cells that breaks down bone tissue), osteoblasts (cells that make bone tissue), and mesenchymal stem cells (MSCs), which are precursors to osteoblasts.
Researchers set out to investigate whether bone disease can be attributed to the high levels of sphingolipids in patients with Gaucher disease.
They tested the effects of sphingolipids on osteoclasts, osteoblasts, and MSCs obtained from Gaucher patients and healthy individuals (controls). They also tested their effects in the human osteoblast cell line SaOS-2.
Sphingolipids included sphingosine, sphingosine-1-phosphate, glucosylsphingosine, ceramide, lactosylceramide, and glucoylceramide.
The majority of sphingolipids did not affect any of the cell lines with the exception of glucosylsphingosine — which reduced the number of MSCs and SaOS-2. This could explain the decrease in bone mineral density in Gaucher patients.
Interestingly, treatment with enzyme replacement therapy has been shown to reduce glucosylsphingosine, which may be part of the reason for the gradual increase in bone mineral density that is observed in treated Gaucher patients.
Additionally, calcium deposition by osteoblasts from GD patients decreased significantly in the presence of two sphingolipids — lactosylceramides and glucosylceramides — indicating a deficiency in making bone.
Investigators suggest this is likely due to a reduction in numbers of available MSCs, a decrease in the production of osteoblasts from MSCs, as well as a decrease in osteoblast function.
Researchers also wanted to investigate the potential roles of sphingolipids in osteoclastogenesis (the production of osteoclasts). They found that the addition of sphingosine to osteoclast cells led to a significant decrease in osteoclast generation while the addition of lactosylceramide or glucosylceramide led to a significant increase in osteoclasts.
Researchers did not observe a significant difference between the effect of these sphingolipids between controls and Gaucher patients in terms of osteoclastogenesis.
However, they explain that cells were only exposed to sphingolipids for 21 days in the laboratory, which is not representative of how long cells are exposed to sphingolipids in the human body. This represents a limitation of the data.
The study’s findings suggest that sphingolipids play an important role in regulating the balance between bone formation and bone degradation. Therefore, an imbalance in sphingolipid levels can lead to bone disease.
“Our work suggests that bioactive sphingolipids may have an important role in bone density,” researchers wrote. “However, further work is required to fully establish this.”