Enzyme replacement therapy reduces Gaucher cell burden but may accelerate osteopenia in patients with type I disease – a histological study

Rudzki, Zbigniew; Okoń, Krzysztof; Machaczka, Maciej; Rucinska, Malgorzata; Papla, B; Skotnicki, Aleksander B.

doi:10.1034/j.1600-0609.2003.00047.x

Cited by 30 publications

(18 citation statements)

References 28 publications

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“…As for the relationship between ERT and GC, it is suggested here that ERT represents prevention of GC induction by its positive influence on monocytes able to endocytose effectively the applied enzyme (Sato and Beutler 1993). This is in accord with the observation of decreased number of GCs during ERT (Rudzki et al 2003). The effect of ERT on the monocyte-histiocytic lineage could thus be better evaluated by measuring the increasing proportion of nonstorage macrophages.…”

Section: Enzyme Replacement Therapy (Ert)supporting

confidence: 60%

Glucosylceramide transfer from lysosomes—the missing link in molecular pathology of glucosylceramidase deficiency: A hypothesis based on existing data

Elleder

2006

J of Inher Metab Disea

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SummaryGaucher disease (GD), deficiency of acid glucosylceramidase (GlcCer‐ase) is characterized by deficient degradation of beta‐glucosylceramide (GlcCer). It is well known that, in GD, the lysosomal accumulation of uncleaved GlcCer is limited to macrophages, which are gradually converted to storage cells with well known cytology—Gaucher cells (GCs). On the basis of previous studies of the disorder and of a comparison with other lysosomal enzymopathies affecting degradation of the GlcCer‐based glycosphingolipid series, it is hypothesized that in other cell types (i.e. non‐macrophage cells) the uncleaved GlcCer, in GlcCer‐ase deficiency, is transferred to other cell compartments, where it may be processed and even accumulated to various degrees. The consequence of the abnormal extralysosomal load may differ according to the cell type and compartment targeted and may be influenced by genetically determined factors, by a number of acquired conditions, including the current metabolic situation. The sequelae of the uncleaved GlcCer extralysosomal transfer may range from probably innocent or positive stimulatory, to the much more serious, in which it interferes with a variety of cell functions, and in extreme cases, can lead to cell death. This alternative processing of uncleaved GlcCer may help to explain tissue alterations seen in GD that have, so far, resisted explanation based simply on the presence of GCs. Paralysosomal alternative processing may thus go a long way towards filling a long‐standing gap in the understanding of the molecular pathology of the disorder. The impact of this alternative process will most likely be inversely proportional to the level of residual GlcCer‐ase activity. Lysosomal sequestration of GlcCer in these cells is either absent or in those exceptional cases where it does occur, it is exceptional and rudimentary. It is suggested that paralysosomal alternative processing of uncleaved GlcCer is the main target for enzyme replacement therapy. The mechanism responsible for GlcCer transfer remains to be elucidated. It may also help in explaining the so far unclear origin of glucosylsphingosine (GlcSph) and define the mutual relation between these two processes.

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Section: Enzyme Replacement Therapy (Ert)supporting

confidence: 60%

Glucosylceramide transfer from lysosomes—the missing link in molecular pathology of glucosylceramidase deficiency: A hypothesis based on existing data

Elleder

2006

J of Inher Metab Disea

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“…In correlation with the reduction of bone symptoms, ERT has been shown to have a significant positive effect on the quality of life of GD patients with skeletal disease after 2 years of treatment [101]. Finally, Rudzki et al [101] evaluated also bone marrow biopsies prior to and after 26-32 months of ERT.…”

Section: Imiglucerasementioning

confidence: 99%

“…Finally, Rudzki et al [101] evaluated also bone marrow biopsies prior to and after 26-32 months of ERT. The effect was mainly achieved by the reduction of Gaucher cell burden, the disappearance of Gaucher cells, and, but only partially, by the shrinkage of Gaucher cells.…”

Section: Imiglucerasementioning

confidence: 99%

Gaucher Disease and Bone Manifestations

et al. 2014

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Gaucher disease is a relatively rare metabolic disease caused by the inherited deficiency of the lysosomal enzyme glucocerebrosidase. Gaucher disease affects multiple organs, among which is the skeleton. Bone involvement occurs frequently in Gaucher disease, and is one of its most debilitating features, reducing the quality of life of patients. Bone status is an important consideration for treatment to ameliorate symptoms and reduce the risk of irreversible complications. We have conducted a systematic review of all the various aspects of Gaucher disease, focusing on different skeletal manifestations, pathophysiology of bone alterations, clinical symptoms, and current diagnostic and therapeutic approaches.

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“…15,16 Recent data have shown both bone marrow and hematopoietic abnormalities in GD, and bone marrow infiltration by Gaucher cells was observed in GD patients. [17][18][19][20] It has also been reported that GD may affect the growth of erythroid progenitors and myelopoiesis of induced pluripotent stem cells (iPSCs). 21 Moreover, an important extramedullary hematopoiesis with the presence of erythroid cells was observed in the spleen of a murine model of GD.…”

Section: Introductionmentioning

confidence: 99%

Unexpected macrophage-independent dyserythropoiesis in Gaucher disease

et al. 2016

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International audienceGaucher disease is a rare inherited disease caused by a deficiency in glucocerebrosidase leading to lipid accumulation in cells of mononuclear-macrophage lineage known as Gaucher cells. Visceral enlargement, bone involvement, mild anemia and thrombocytopenia are the major manifestations of Gaucher disease. We have previously demonstrated that the red blood cells from patients exhibit abnormal properties, which indicates a new role in Gaucher disease pathophysiology. To investigate whether erythroid progenitors are affected, we examined the in vitro erythropoiesis from the peripheral CD34+ cells of patients and controls. CD34− cells were differentiated into macrophages and co-cultivated with erythroblasts. We showed an accelerated differentiation of erythroid progenitors without maturation arrest from patients compared to controls. This abnormal differentiation persisted in the patients when the same experiments were performed without macrophages, which strongly suggested that dyserythropoiesis in Gaucher disease is secondary to an inherent defect in the erythroid progenitors. The accelerated differentiation was associated with reduced cell proliferation. As a result, less mature erythroid cells were generated in vitro in the Gaucher disease cultures compared to the control. We then compared the biological characteristics of untreated patients according to their anemic status. Compared to the non-anemic group, the anemic patients exhibit higher plasma levels of growth differentiation factor-15, a marker of ineffective erythropoiesis, but they had no indicators of hemolysis and similar reticulocyte counts. Taken together, these results demonstrated an unsuspected dyserythropoiesis that was independent of the macrophages and could participate, at least in part, to the basis of anemia in Gaucher disease

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Enzyme replacement therapy reduces Gaucher cell burden but may accelerate osteopenia in patients with type I disease – a histological study

Cited by 30 publications

References 28 publications

Glucosylceramide transfer from lysosomes—the missing link in molecular pathology of glucosylceramidase deficiency: A hypothesis based on existing data

Glucosylceramide transfer from lysosomes—the missing link in molecular pathology of glucosylceramidase deficiency: A hypothesis based on existing data

Gaucher Disease and Bone Manifestations

Unexpected macrophage-independent dyserythropoiesis in Gaucher disease

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