The role of sphingolipid metabolism in sickle bone disease and bone stem cells
Selma, Jada M.
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Sickle cell disease (SCD) is the most common inherited blood disorder in the United States. SCD affects approximately 100,000 people domestically and an additional 300,000 babies born globally every year. A collection of pathologies, including osteonecrosis (ON), osteoporosis, and osteopenia, known as sickle bone disease (SBD) are among the most common complications of SCD, which progresses from adolescence and occurs in 50% of individuals by age 35. Transgenic sickle mouse model studies have shown that increased osteoclast activity and reduced mesenchymal stem cell (MSC) differentiation into osteoblasts contributes broadly to pathological bone remodeling in SCD, but underlying cellular and molecular mechanisms are poorly understood. Sphingosine 1-phosphate (S1P), a type of sphingolipid, directs a wide array of cellular processes involved in bone homeostasis including directing MSCs towards an osteogenic lineage and modulating their migration. S1P also regulates osteoclastogenesis and is linked to the activity of cathepsin K (cat K), a protease secreted by osteoclasts to resorb bone. We have previously shown that dysregulated sphingolipid metabolism in SCD leads to increased S1P in sickle patients’ blood, plasma, and erythrocytes. Monocytes isolated from people with SCD are primed for inflammation and cat K proteolytic activity induction when binding to endothelial cells. Cat K-induced bone resorption mechanisms are implicated in bone dysfunction without SCD but have not been mechanistically linked to SCD osteopathologies. The objective of this research is to investigate the relationship between sphingolipid metabolism and cathepsin activation in SCD. It is also the aim of this work to utilize sphingolipid signaling as a potential therapy for SBD. It is hypothesized that dysregulated sphingolipid metabolism leads to bone loss in SCD that is propagated by increased cathepsin activity and that bone loss can be mitigated by cathepsin inhibition. This study utilizes a transgenic mouse model to characterize the sickle bone phenotype and to test the effect of a cathepsin inhibitor on bone morphology. This research further utilizes a S1P analog in wild-type mice to investigate if mobilizing MSCs out of the bone marrow can aid in bone repair. Elucidation of how dysregulated sphingolipid metabolism contributes to increased proteolytic activity in SCD that leads to increased bone resorption will better inform clinical therapeutic strategies to prevent detrimental bone loss in sickle cell patients.