Effect of glycosphingolipids on osteoclastogenesis and osteolytic bone diseases

Ersek, Adel; Karadimitris, Anastasios; Horwood, Nicole J.

doi:10.3389/fendo.2012.00106

Cited by 7 publications

(8 citation statements)

References 65 publications

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“…15 Interestingly, glucosylsphingosine, which is a known osteoblastic toxin, 36 was markedly reduced by eliglustat therapy. Of note, GM3, which plays a role in osteoclast differentiation, 40 was also markedly reduced with eliglustat therapy. Collaborative Gaucher Group (ICGG) Gaucher Registry, 41 this study supports the use of eliglustat as first-line treatment for previously untreated patients with GD1 without the need for "debulking" with ERT.…”

Section: Safetymentioning

confidence: 95%

Clinical outcomes after 4.5 years of eliglustat therapy for Gaucher disease type 1: Phase 3 ENGAGE trial final results

et al. 2021

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Eliglustat, an oral substrate reduction therapy, is approved for eligible adults with Gaucher disease type 1. In the Phase 3 ENGAGE trial of previously untreated adults with Gaucher disease type 1, eliglustat-treated patients had statistically significant improvements in organ volumes and hematologic parameters compared with placebo in the 9-month primary analysis. We report final outcomes by time on eliglustat among all patients who participated in the ENGAGE trial and extension. No patient deteriorated clinically or withdrew due to adverse events; 39/40 patients entered the open-label Clinical trial registration: NCT00891202

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Section: Safetymentioning

confidence: 95%

Clinical outcomes after 4.5 years of eliglustat therapy for Gaucher disease type 1: Phase 3 ENGAGE trial final results

et al. 2021

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“…Plasma membrane is a highly dynamic structure composed of phospholipid bilayer and lipid rafts, being one of the main structures of all living systems, delimiting cells and organelles such as lysosomes and mitochondria. Lipid rafts are composed of cholesterol, glycosphingolipids, and specific proteins, which are associated and dissociated in the second scale [27][28][29].…”

Section: Biological Membrane Alterationmentioning

confidence: 99%

“…These microdomains are involved in cellular signaling and membrane permeability, such as endo-and exocytosis during bacterial or toxin aggression [30,31], immune cell activation [32], redox signaling [33,34], osteoclastogenesis induction [28,35], and insulin secretion and sensitivity [32,36]. The type and amount of lipids vary in each cell membrane according to their function and the individual's diet and are influenced by lipid metabolism in health and disease condition.…”

Section: Biological Membrane Alterationmentioning

confidence: 99%

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Diabetes Mellitus and Periodontitis Share Intracellular Disorders as the Main Meeting Point

Portes

Bullón

Quiles

et al. 2021

Cells

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Diabetes and periodontitis are two of the most prevalent diseases worldwide that negatively impact the quality of life of the individual suffering from them. They are part of the chronic inflammatory disease group or, as recently mentioned, non-communicable diseases, with inflammation being the meeting point among them. Inflammation hitherto includes vascular and tissue changes, but new technologies provide data at the intracellular level that could explain how the cells respond to the aggression more clearly. This review aims to emphasize the molecular pathophysiological mechanisms in patients with type 2 diabetes mellitus and periodontitis, which are marked by different impaired central regulators including mitochondrial dysfunction, impaired immune system and autophagy pathways, oxidative stress, and the crosstalk between adenosine monophosphate-activated protein kinase (AMPK) and the renin-angiotensin system (RAS). All of them are the shared background behind both diseases that could explain its relationship. These should be taken in consideration if we would like to improve the treatment outcomes. Currently, the main treatment strategies in diabetes try to reduce glycemia index as the most important aspect, and in periodontitis try to reduce the presence of oral bacteria. We propose to add to the therapeutic guidelines the handling of all the intracellular disorders to try to obtain better treatment success.

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“…However, miglustat is involved in various biological and pathological pathways and can cause deleterious side effects in the gastrointestinal track including severe diarrhea and weight loss 17 . Eliglustat, a small synthetic molecule, specifically prevents the synthesis of all GSLs by inhibition of glucosylceramide synthase (GCS) 18 and is used for the treatment of Gaucher disease type 1 in adults 19 . Gaucher patients suffer from osteoporosis/osteopenia and treatment to reduce excess bioactive GSL associated with the disease has been shown to alleviate bone loss 20 .…”

Section: Introductionmentioning

confidence: 99%

Improving bone health via modulation of glycosphingolipid metabolism and autophagy

Leng

Zhang

et al. 2021

Preprint

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Patients with multiple myeloma (MM), an incurable malignancy of plasma cells, frequently develop osteolytic bone lesions. In this study, glycosphingolipids were essential in promoting autophagic degradation of the signaling molecule TRAF3, a key step in bone-resorbing osteoclast differentiation. Specifically altering the glycosphingolipid composition with eliglustat, an FDA approved glucosylceramide synthase inhibitor, arrested osteoclast differentiation; this could be rescued by exogenous addition of the missing glycosphingolipids. Eliglustat significantly reduced bone disease in several preclinical models of MM by inhibiting osteoclastogenesis and, due to its unique mode of action, it was able to act in combination with existing bone protective drugs. Furthermore, eliglustat arrested osteoclast differentiation from the bone marrow of MM patients in a glycosphingolipid-dependent way. This work identifies both the mechanism by which glucosylceramide synthase inhibition blocks autophagic degradation of TRAF3 to reduce osteoclastogenesis as well as highlighting the translational potential of eliglustat to be combined with current treatments.

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Effect of glycosphingolipids on osteoclastogenesis and osteolytic bone diseases

Cited by 7 publications

References 65 publications

Clinical outcomes after 4.5 years of eliglustat therapy for Gaucher disease type 1: Phase 3 ENGAGE trial final results

Clinical outcomes after 4.5 years of eliglustat therapy for Gaucher disease type 1: Phase 3 ENGAGE trial final results

Diabetes Mellitus and Periodontitis Share Intracellular Disorders as the Main Meeting Point

Improving bone health via modulation of glycosphingolipid metabolism and autophagy

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