Elevation of glycoprotein nonmetastatic melanoma protein B in type 1 Gaucher disease patients and mouse models

Kramer, Gertjan; Wegdam, Wouter; Donker‐Koopman, Wilma E.; Ottenhoff, Roelof; Gaspar, Paulo; Verhoek, Marri; Nelson, Jessica K.; Gabriel, Tanit L.; Kallemeijn, Wouter W.; Boot, Rolf G.; Laman, Jon D.; Vissers, Johannes P.C.; Cox, Timothy M.; Pavlova, Elena; Moran, Mary Teresa; Aerts, Johannes M. F. G.; Eijk, Marco van

doi:10.1002/2211-5463.12078

Cited by 56 publications

(68 citation statements)

References 51 publications

(71 reference statements)

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“…In mice with conditional deficiency in GCase in the white blood cell lineage Gaucher-like cells are formed. These do not produce chitotriosidase or CCL18, but gpNMB does [140,144]. Inactivation of GCase with an irreversible inhibitor was found to increase gpNMB in the brain [143].…”

Section: Lysosomal Glccer Deposits In Macrophages: Gaucher Cellsmentioning

confidence: 94%

“…The chemokine is over-produced and secreted by Gaucher cells [139]. More recently the glycoprotein nonmetastatic melanoma protein B (gpNMB) was found to be overproduced by Gaucher cells [140]. A soluble fragment of gpNMB is released into plasma and is over 50-fold elevated in type 1 GD patients [140,141].…”

Section: Lysosomal Glccer Deposits In Macrophages: Gaucher Cellsmentioning

confidence: 99%

“…More recently the glycoprotein nonmetastatic melanoma protein B (gpNMB) was found to be overproduced by Gaucher cells [140]. A soluble fragment of gpNMB is released into plasma and is over 50-fold elevated in type 1 GD patients [140,141]. In cerebral spine fluid and brain of type 3 GD patients elevated gpNMB levels have also been observed [142].…”

Section: Lysosomal Glccer Deposits In Macrophages: Gaucher Cellsmentioning

confidence: 99%

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Glucocerebrosidase: Functions in and Beyond the Lysosome

Boer

Smeden

Bouwstra

et al. 2020

JCM

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Glucocerebrosidase (GCase) is a retaining β-glucosidase with acid pH optimum metabolizing the glycosphingolipid glucosylceramide (GlcCer) to ceramide and glucose. Inherited deficiency of GCase causes the lysosomal storage disorder named Gaucher disease (GD). In GCase-deficient GD patients the accumulation of GlcCer in lysosomes of tissue macrophages is prominent. Based on the above, the key function of GCase as lysosomal hydrolase is well recognized, however it has become apparent that GCase fulfills in the human body at least one other key function beyond lysosomes. Crucially, GCase generates ceramides from GlcCer molecules in the outer part of the skin, a process essential for optimal skin barrier property and survival. This review covers the functions of GCase in and beyond lysosomes and also pays attention to the increasing insight in hitherto unexpected catalytic versatility of the enzyme.

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Section: Lysosomal Glccer Deposits In Macrophages: Gaucher Cellsmentioning

confidence: 94%

Section: Lysosomal Glccer Deposits In Macrophages: Gaucher Cellsmentioning

confidence: 99%

Section: Lysosomal Glccer Deposits In Macrophages: Gaucher Cellsmentioning

confidence: 99%

See 1 more Smart Citation

Glucocerebrosidase: Functions in and Beyond the Lysosome

Boer

Smeden

Bouwstra

et al. 2020

JCM

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“…Deregulation of proteinase activity has already been observed in patients with GD that could contribute to the excretion of some proteins . The biomarker gpNMB / osteocactivin allowing to discriminate patients with GD from healthy subjects have been recently discovered . As Sema7A, the soluble form of gpNMB is present in higher concentrations in the plasma of GD patients and the expression of this biomarker was also increased in the splenic macrophages of the patients.…”

Section: Discussionmentioning

confidence: 99%

Semaphorin 7A: A novel marker of disease activity in Gaucher disease

et al. 2020

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Gaucher disease (GD) is a recessively inherited lysosomal storage disorder in which sphingolipids accumulates in the macrophages that transform into Gaucher cells. A growing body of evidence indicates that red blood cells (RBCs) represent important actors in GD pathophysiology. We previously demonstrated that altered RBC properties including increased Lyso-GL1 levels, dyserythropoiesis, and iron metabolism defect in GD patients contribute to anemia and hyperferritinemia. Since RBC defects also correlated well with markers of GD severity and were normalized under enzyme replacement therapy (ERT), the identification of molecules that are deregulated in GD RBCs represents an important issue in the search of pertinent markers of the disease.

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“…Of interest, lysosomal stress also occurs in inherited disorders in intralysosomal sphingolipid catabolism, either caused by a deficiency in a lysosomal glycosphingolipid hydrolase such as glucocerebrosidase in Gaucher disease or by a generalized lysosome dysfunction as in Niemann-Pick type C disease. Both in Gaucher disease and Niemann-Pick type C disease Gpnmb has also been found to be markedly induced [ 19 – 21 ]. These findings suggest that impaired lysosomal sphingolipid metabolism induces lysosome biogenesis and might be considered to also occur in obese ATMs.…”

Section: Introductionmentioning

confidence: 99%

Induction of Sphk1 activity in obese adipose tissue macrophages promotes survival

et al. 2017

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During obesity, adipose tissue macrophages (ATM) are increased in concert with local inflammation and insulin resistance. Since the levels of sphingolipid (SLs) in adipose tissue (AT) are altered during obesity we investigated the potential impact of SLs on ATMs. For this, we first analyzed expression of SL metabolizing genes in ATMs isolated from obese mice. A marked induction of sphingosine kinase 1 (Sphk1) expression was observed in obese ATM when compared to lean ATM. This induction was observed in both MGL-ve (M1) and MGL1+ve (M2) macrophages from obese WAT. Next, RAW264.7 cells were exposed to excessive palmitate, resulting in a similar induction of Sphk1. This Sphk1 induction was also observed when cells were treated with chloroquine, a lysosomotropic amine impacting lysosome function. Simultaneous incubation of RAW cells with palmitate and the Sphk1 inhibitor SK1-I promoted cell death, suggesting a protective role of Sphk1 during lipotoxic conditions. Interestingly, a reduction of endoplasmic reticulum (ER) stress related genes was detected in obese ATM and was found to be associated with elevated Sphk1 expression. Altogether, our data suggest that lipid overload in ATM induces Sphk1, which promotes cell viability.

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Elevation of glycoprotein nonmetastatic melanoma protein B in type 1 Gaucher disease patients and mouse models

Cited by 56 publications

References 51 publications

Glucocerebrosidase: Functions in and Beyond the Lysosome

Glucocerebrosidase: Functions in and Beyond the Lysosome

Semaphorin 7A: A novel marker of disease activity in Gaucher disease

Induction of Sphk1 activity in obese adipose tissue macrophages promotes survival

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