Unraveling the mystery of Gaucher bone density pathophysiology

Rozenfeld, Paula; Crivaro, Andrea; Ormazabal, Maximiliano; Mucci, Juan Marcos; Bondar, Constanza; Delpino, M. Victoria

doi:10.1016/j.ymgme.2020.07.011

Cited by 7 publications

(6 citation statements)

References 112 publications

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“…Considering the interaction between immune and bone systems [ 18 ] and the fact that several proinflammatory cytokines, including interleukin-1β (IL-1β), tumor necrosis factor α (TNF-α), and interleukin-6 (IL-6), are elevated in patients with GD and several in vitro disease models [ 30 , 37 , 38 , 39 ], we decided to examine the pro-inflammatory profile in monocyte GBAKO-THP1 cells. Therefore, we assessed the levels of IL-1β, TNF-α, and IL-6 secreted by the cells into the culture media.…”

Section: Resultsmentioning

confidence: 99%

“…Skeletal alterations are one of the most disabling features in GD patients nowadays and are not completely resolved with currently available specific therapies. Both defective bone formation and increased bone resorption due to activated osteoclastogenesis have been demonstrated to contribute to GD bone pathology [ 15 , 18 , 20 , 21 , 43 ].…”

Section: Discussionmentioning

confidence: 99%

“…Chronic stimulation of the immune system is a hallmark of many lysosomal disorders, including GD, and it is characterized by a markedly elevated level of proinflammatory cytokines, such as Interleukin-1β (IL-1β), Tumor Necrosis Factor- α (TNF-α), and/or Interleukin-6 (IL-6), and chemokines [ 17 ]. A possible pathogenic role of the immune system in bone pathology has been proposed since it has been demonstrated that inflammation may have a negative impact on bone homeostasis by targeting osteoclasts, osteoblasts, and osteocytes [ 18 ]. Indeed, two cytokines, macrophage colony-stimulating factor (M-CSF) and receptor activator of nuclear factor κB ligand (RANKL), are absolutely required for osteoclast differentiation.…”

Section: Introductionmentioning

confidence: 99%

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Exploring the Pathophysiologic Cascade Leading to Osteoclastogenic Activation in Gaucher Disease Monocytes Generated via CRISPR/Cas9 Technology

Ormazabal

Pavan

Vaena

et al. 2023

IJMS

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Gaucher disease (GD) is caused by biallelic pathogenic variants in the acid β-glucosidase gene (GBA1), leading to a deficiency in the β-glucocerebrosidase (GCase) enzyme activity resulting in the intracellular accumulation of sphingolipids. Skeletal alterations are one of the most disabling features in GD patients. Although both defective bone formation and increased bone resorption due to osteoblast and osteoclast dysfunction contribute to GD bone pathology, the molecular bases are not fully understood, and bone disease is not completely resolved with currently available specific therapies. For this reason, using editing technology, our group has developed a reliable, isogenic, and easy-to-handle cellular model of GD monocytes (GBAKO-THP1) to facilitate GD pathophysiology studies and high-throughput drug screenings. In this work, we further characterized the model showing an increase in proinflammatory cytokines (Interleukin-1β and Tumor Necrosis Factor-α) release and activation of osteoclastogenesis. Furthermore, our data suggest that GD monocytes would display an increased osteoclastogenic potential, independent of their interaction with the GD microenvironment or other GD cells. Both proinflammatory cytokine production and osteoclastogenesis were restored at least, in part, by treating cells with the recombinant human GCase, a substrate synthase inhibitor, a pharmacological chaperone, and an anti-inflammatory compound. Besides confirming that this model would be suitable to perform high-throughput screening of therapeutic molecules that act via different mechanisms and on different phenotypic features, our data provided insights into the pathogenic cascade, leading to osteoclastogenesis exacerbation and its contribution to bone pathology in GD.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Exploring the Pathophysiologic Cascade Leading to Osteoclastogenic Activation in Gaucher Disease Monocytes Generated via CRISPR/Cas9 Technology

Ormazabal

Pavan

Vaena

et al. 2023

IJMS

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“…Reduced bone density is common in GD. In fact, the most common bone lesions in this entity are medullary infiltration and osteopenia [ 41 , 42 ]. Data from the ICGG Gaucher Registry also indicate that 55% of all patients affected by this lysosomal disease have osteopenia [ 43 ].…”

Section: Adulthoodmentioning

confidence: 99%

Women with Gaucher Disease

Meijon-Ortigueira,

Solares,

Muñoz-Delgado

et al. 2024

Biomedicines

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Gaucher disease is an inherited disorder in which there is a deficiency of the enzyme glucocerebrosidase, which leads to the accumulation of glucosylceramide. Although much scientific evidence is now available, there is still limited data on the impact on the different life stages of women with this disease. Among other alterations, a delay in menarche has been described, although it has not been related to fertility problems. Menorrhagia is relatively frequent, being related to the presence of thrombocytopenia, thrombocytopathies or coagulation disorders. On the other hand, pregnancy planning is an increasingly frequent concern. All patients should undergo genetic counseling, and it is important to monitor the appearance or worsening of organomegaly, bone and hematologic abnormalities to establish clinical and therapeutic recommendations. Management during the puerperium will depend on the evolution of gestation, and, during the lactation period, the potential appearance of bone complications should be assessed. An early onset of menopause, compared to the general population, has also been described, which may accelerate the development of osteopenia. Finally, although the usual screening protocols for neoplasms are currently being performed, it is recommended to watch for early signs of liver or renal neoplasms when examining the results of imaging tests performed during evaluations for this disease.

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“…Types II and III are neuronopathic, whereas type I (the most frequent presentation in Western countries), lacks early neuropathology and is characterized by splenomegaly, hepatomegaly, anemia, thrombocytopenia, and skeletal complications that include acute or chronic pain, avascular necrosis, osteoarthritis, osteopenia and osteoporosis. The pathophysiology of skeletal density affection in GD is matter of intense research due to the diverse mechanisms that could be involved, including rate of bone remodeling, development and differentiation of mesenchymal stem cells (MSCs) and osteoimmunology [ 1 ].…”

Section: Introductionmentioning

confidence: 99%