Effect of Substrate Reduction Therapy in Comparison to Enzyme Replacement Therapy on Immune Aspects and Bone Involvement in Gaucher Disease

Limgala, Renuka P.; Göker-Alpan, Özlem

doi:10.3390/biom10040526

Cited by 14 publications

(10 citation statements)

References 26 publications

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“…However, in another study, there were decreased OPG and RANKL/OPG levels in GD [6]. Our group has previously demonstrated that plasma RANKL and OPG levels decreased in SRT-treated patients over time, but RANKL/OPG did not change with the treatment status [41].…”

Section: K E L I G a N D 1mentioning

confidence: 74%

TRAP5b and RANKL/OPG Predict Bone Pathology in Patients with Gaucher disease

Ivanova

Dao

Noll

et al. 2021

Preprint

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Bone involvement occurs in 75% of patients with Gaucher disease (GD), and comprises structural changes, debilitating pain, and bone density abnormalities. Osteoporosis is a silent manifestation of GD until a pathologic fracture occurs. Thus early diagnosis is crucial for identifying high-risk patients to prevent irreversible complications. Thirty-one patients with GD were assessed prospectively to identify predictive markers associated with bone density abnormalities, osteopenia (OSN), and osteoporosis (OSR). Subjects were categorized into three cohorts based on T- or Z- scores of bone mineral density (BMD): In GD cohort with no bone complication (Z-score≥-0.9; T-scores≥-1), the OSN group (-1.8 ≥ Z-score ≥ -1; -2.5 ≥ T-score ≥ -1) and OSR group (Z-score ≤ -1.9; T-scores ≤ -2.5). Serum levels of TRAP5b, RANKL, OPG, and RANK were quantified by enzyme-linked immunosorbent assays. TRAP5b was increased in GD and showed a positive correlation with GD biomarkers, including plasma glucosylsphingosine (Lyso-Gb1), macrophage activation markers CCL18 and chitotriosidase. The highest levels of TRAP5b was measured in patients with osteoporosis. The elevation of RANKL and RANKL/OPG ratio correlated with osteopenia in GD. Elevation of TRAP5b, RANKL, and RANKL/OPG indicate osteoclast activation in GD. TRAP5b is a potential bone biomarker for GD with the ability to predict the progression of bone density abnormalities.

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Section: K E L I G a N D 1mentioning

confidence: 74%

TRAP5b and RANKL/OPG Predict Bone Pathology in Patients with Gaucher disease

Ivanova

Dao

Noll

et al. 2021

Preprint

Self Cite

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“…The most common bone lesions are medular infiltration and osteopenia [6]. Another research including 32 Gaucher patients, which most of them were on specific treatment, showed significant bone manifestations: 72% of subjects presented with radiological changes, 59% reported bone pain and 50% with diminished bone density [7]. A recent study has used the trabecular bone score to characterize bone micro-architecture and its macroscopic geometry, which revealed an altered score in all of the patients assayed [8], even in those who have normal bone mineral density assessed by densitometry.…”

Section: Skeletal Manifestations In Gaucher Patientsmentioning

confidence: 99%

Unraveling the mystery of Gaucher bone density pathophysiology

Rozenfeld¹,

Crivaro²,

Ormazabal³

et al. 2021

Molecular Genetics and Metabolism

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This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

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“…Currently, the primary treatment for the visceral abnormalities of GD is enzyme replacement therapy (ERT) with recombinant glucocerebrosidase (rGCase), and more recently, substrate reduction therapy (SRT) with GluCer synthase inhibitors [ 1 , 19 ]. However, ERT and SRT do not completely prevent inflammation, the increased risk of malignancies, or the hepatic fibrosis associated with GD [ 20 , 21 , 22 , 23 , 24 , 25 , 26 ]. Complement inhibitors have shown recent promise as an adjunctive therapy for GD in murine models, but their biological mechanisms of action remain unknown [ 21 , 27 ].…”

Section: Introductionmentioning

confidence: 99%

C5a Activates a Pro-Inflammatory Gene Expression Profile in Human Gaucher iPSC-Derived Macrophages

Serfecz

Saadin

Santiago

et al. 2021

IJMS

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Gaucher disease (GD) is an autosomal recessive disorder caused by bi-allelic GBA1 mutations that reduce the activity of the lysosomal enzyme β-glucocerebrosidase (GCase). GCase catalyzes the conversion of glucosylceramide (GluCer), a ubiquitous glycosphingolipid, to glucose and ceramide. GCase deficiency causes the accumulation of GluCer and its metabolite glucosylsphingosine (GluSph) in a number of tissues and organs. In the immune system, GCase deficiency deregulates signal transduction events, resulting in an inflammatory environment. It is known that the complement system promotes inflammation, and complement inhibitors are currently being considered as a novel therapy for GD; however, the mechanism by which complement drives systemic macrophage-mediated inflammation remains incompletely understood. To help understand the mechanisms involved, we used human GD-induced pluripotent stem cell (iPSC)-derived macrophages. We found that GD macrophages exhibit exacerbated production of inflammatory cytokines via an innate immune response mediated by receptor 1 for complement component C5a (C5aR1). Quantitative RT-PCR and ELISA assays showed that in the presence of recombinant C5a (rC5a), GD macrophages secreted 8–10-fold higher levels of TNF-α compared to rC5a-stimulated control macrophages. PMX53, a C5aR1 blocker, reversed the enhanced GD macrophage TNF-α production, indicating that the observed effect was predominantly C5aR1-mediated. To further analyze the extent of changes induced by rC5a stimulation, we performed gene array analysis of the rC5a-treated macrophage transcriptomes. We found that rC5a-stimulated GD macrophages exhibit increased expression of genes involved in TNF-α inflammatory responses compared to rC5a-stimulated controls. Our results suggest that rC5a-induced inflammation in GD macrophages activates a unique immune response, supporting the potential use of inhibitors of the C5a-C5aR1 receptor axis to mitigate the chronic inflammatory abnormalities associated with GD.

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Effect of Substrate Reduction Therapy in Comparison to Enzyme Replacement Therapy on Immune Aspects and Bone Involvement in Gaucher Disease

Cited by 14 publications

References 26 publications

TRAP5b and RANKL/OPG Predict Bone Pathology in Patients with Gaucher disease

TRAP5b and RANKL/OPG Predict Bone Pathology in Patients with Gaucher disease

Unraveling the mystery of Gaucher bone density pathophysiology

C5a Activates a Pro-Inflammatory Gene Expression Profile in Human Gaucher iPSC-Derived Macrophages

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