Proinflammatory and proosteoclastogenic potential of peripheral blood mononuclear cells from Gaucher patients: Implication for bone pathology

Mucci, Juan Marcos; Cuello, María Fernanda; Kisinovsky, Isaac; Larroudé, M.S.; Delpino, M. Victoria; Rozenfeld, Paula

doi:10.1016/j.bcmd.2015.05.009

Cited by 25 publications

(33 citation statements)

References 42 publications

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“…The M2 subpopulation has been described as cells with anti-inflammatory, immunomodulatory and tissue repair properties, and includes macrophages that remove abnormal hematopoietic cells or phagocytose erythroblast nuclei. The in vivo situation appears more complex since the plasma cytokine profile and the characteristic monocytes circulating in the blood show concurrent activation of inflammatory M1 macrophages, presumably implicated in the “pseudo-inflammatory” state that was described many years ago and in the heterogeneous manifestations of the disease [12,13]. Thus numerous cytokines, chemokines and other molecules—including IL-1β, IL-6, IL-8, TNFα (Tumor Necrosis Factor), M-CSF (Macrophage-Colony Stimulating Factor), MIP-1β, IL-18, IL-10, TGFβ, CCL-18, chitotriosidase, CD14s, and CD163s—are present in increased amounts in Gaucher patients’ plasma and could be implicated in hematological and bone complications [14,15,16,17].…”

Section: Pathophysiologymentioning

confidence: 99%

A Review of Gaucher Disease Pathophysiology, Clinical Presentation and Treatments

Stirnemann¹,

Belmatoug

Camou

et al. 2017

IJMS

552

627

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Gaucher disease (GD, ORPHA355) is a rare, autosomal recessive genetic disorder. It is caused by a deficiency of the lysosomal enzyme, glucocerebrosidase, which leads to an accumulation of its substrate, glucosylceramide, in macrophages. In the general population, its incidence is approximately 1/40,000 to 1/60,000 births, rising to 1/800 in Ashkenazi Jews. The main cause of the cytopenia, splenomegaly, hepatomegaly, and bone lesions associated with the disease is considered to be the infiltration of the bone marrow, spleen, and liver by Gaucher cells. Type-1 Gaucher disease, which affects the majority of patients (90% in Europe and USA, but less in other regions), is characterized by effects on the viscera, whereas types 2 and 3 are also associated with neurological impairment, either severe in type 2 or variable in type 3. A diagnosis of GD can be confirmed by demonstrating the deficiency of acid glucocerebrosidase activity in leukocytes. Mutations in the GBA1 gene should be identified as they may be of prognostic value in some cases. Patients with type-1 GD—but also carriers of GBA1 mutation—have been found to be predisposed to developing Parkinson’s disease, and the risk of neoplasia associated with the disease is still subject to discussion. Disease-specific treatment consists of intravenous enzyme replacement therapy (ERT) using one of the currently available molecules (imiglucerase, velaglucerase, or taliglucerase). Orally administered inhibitors of glucosylceramide biosynthesis can also be used (miglustat or eliglustat).

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Section: Pathophysiologymentioning

confidence: 99%

A Review of Gaucher Disease Pathophysiology, Clinical Presentation and Treatments

Stirnemann¹,

Belmatoug

Camou

et al. 2017

IJMS

552

627

View full text Add to dashboard Cite

show abstract

“…dysfunctions on other immune cells (19), would favor bone resorption and inhibit bone formation (20,21). Indeed, increased levels of osteoclast precursors in peripheral blood mononuclear cells (PBMC) from GD patients with higher tendency to differentiate into functional osteoclasts were recently revealed (22,23). In addition, osteopenia caused by reduced bone formation was demonstrated in a murine model of GD (24).…”

Section: Accepted Manuscriptmentioning

confidence: 99%

In vitro osteoclastogenesis from Gaucher patients' cells correlates with bone mineral density but not with Chitotriosidase

Bondar

Mucci

Crivaro

et al. 2017

Bone

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Gaucher disease (GD) is caused by mutations on the gene encoding for the lysosomal enzyme glucocerebrosidase. Type I GD (GD1) patients present anemia, hepatosplenomegaly and bone alterations. In spite of treatment, bone alterations in GD patients persist, including poor bone mineral density (BMD). Mechanisms leading to bone damage are not completely understood, but previous reports suggest that osteoclasts are involved. Chitotriosidase (CHIT) is the most reliable biomarker used in the follow up of patients, although its correlation with bone status is unknown. The aim of this work was to study the pro-osteoclastogenic potential in patients and to evaluate its correlation with CHIT activity levels and clinical parameters. PBMCs from treated patients and healthy controls were cultured in the presence of M-CSF, and mature osteoclasts were counted. BMD, blood CHIT activity and serum levels of CTX, BAP, and cytokines were evaluated in patients. We found that blood CHIT activity and osteoclast differentiation were significantly increased in patients, but no correlation between them was observed. Interestingly, osteoclast numbers but not CHIT, presented a negative correlation with BMD expressed as Z-score. CTX, BAP and serum cytokines involved in bone remodeling were found altered in GD1 patients. These results show for the first time a correlation between osteoclast differentiation and BMD in GD1 patients, supporting the involvement of osteoclasts in the bone pathology of GD1. Our results also suggest that an altered immune response may play an important role in bone damage.

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“…The infiltration of Gaucher cells into the bone marrow, along with the increase of pro-and anti-inflammatory cells in GD -which are highly variable but likely result in a chronic pro-inflammatory state -results in an overall immune dysfunction 20 and a resulting dysfunction of the delicate bone remodeling balance. While the mechanism of the remodeling dysfunction is not completely understood, studies point to an osteoclast-osteoblast uncoupling.…”

Section: Pathophysiology Of Skeletal Manifestationsmentioning

confidence: 99%

“…20,21 To maintain the delicate balance in the bone environment, the final phase of osteoblast differentiation is believed to be carefully controlled 22 as osteoblasts are responsible for stimulating osteoclast differentiation. 23 Studies in osteoimmunology describe this process as a complex interaction between bone cell development and immune cells, and point to activated T-cells as key players in this involvement, given their production of a number of inflammatory cytokines 24 either directly or indirectly regulating the cells involved in the bone turnover balance -shifting in either direction, bone reabsorption or bone generation.…”

Section: Pathophysiology Of Skeletal Manifestationsmentioning

confidence: 99%

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Doença De Gaucher Tipo 1 No Esqueleto: Revisão Da América Latina

2016

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Gaucher disease (GD) is the most prevalent lysosomal storage disease, and is characterized by the accumulation of glucosylceramide and glucosylsphingosine in tissues throughout the body. With the advent of enzyme replacement therapy, the prognosis for patients with GD has dramatically improved. Still, the skeletal manifestations associated with GD respond slowly to enzyme replacement therapy and are the most significant contributor of disease related patient morbidity. This review of bone manifestations in GD presents the most recent theories on its pathophysiology, and gives a systematic review of studies with Latin American patients that report the frequency of bone manifestations and the effects of enzyme replacement therapy on their treatment. We conclude by emphasizing the importance of early identification and proper management at appropriate dosage levels of enzyme replacement therapy to reduce the morbidity caused by GD.Keywords: Gaucher disease; Skeleton; Prevalence; Latin America. RESUMO A doença de Gaucher (DG) é a doença de depósito lisossômico mais prevalente, que se caracteriza pelo acúmulo de glicosilceramida e glucosilesfingosina em todos os tecidos do corpo. Com o advento da terapia de reposição de enzimas, o prognóstico dos pacientes com DG melhorou acentuadamente. Ainda assim, as manifestações esqueléticas associadas à DG respondem lentamente à terapia de reposição de enzimas e são as que contribuem de forma mais significativa para a morbidade do paciente. Esta revisão das manifestações ósseas da DG apresenta as mais recentes teorias sobre a sua fisiopatologia e uma revisão sistemática de estudos com pacientes latino-americanos que relataram a frequência das manifestações ósseas e os efeitos da terapia de reposição de enzimas

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Proinflammatory and proosteoclastogenic potential of peripheral blood mononuclear cells from Gaucher patients: Implication for bone pathology

Cited by 25 publications

References 42 publications

A Review of Gaucher Disease Pathophysiology, Clinical Presentation and Treatments

A Review of Gaucher Disease Pathophysiology, Clinical Presentation and Treatments

In vitro osteoclastogenesis from Gaucher patients' cells correlates with bone mineral density but not with Chitotriosidase

Doença De Gaucher Tipo 1 No Esqueleto: Revisão Da América Latina

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