Uncoupling of osteoblast–osteoclast regulation in a chemical murine model of Gaucher disease

Mucci, Juan Marcos; García, Florencia Suqueli; Francesco, Pablo N. De; Ceci, Romina; Genaro, Silvia Di; Fossati, Carlos A.; Delpino, M. Victoria; Rozenfeld, Paula

doi:10.1016/j.gene.2013.09.072

Cited by 22 publications

(16 citation statements)

References 10 publications

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“…Bone marrow cells from patients with Gaucher's disease have reduced CFU‐F formation and osteoblast differentiation . Previous studies suggested that this bone phenotype is due to intrinsic differences in osteoblast regulation due to the underlying mutation . However, our data suggests that this could be secondary to the macrophage defect itself.…”

Section: Discussioncontrasting

confidence: 50%

“…(32) Previous studies suggested that this bone phenotype is due to intrinsic differences in osteoblast regulation due to the underlying mutation. (33,34) However, our data suggests that this could be secondary to the macrophage defect itself. Interestingly, while enzyme replacement therapy is effective in managing the hematological abnormalities of the disease, its effect on bone health varies, (35) and this could be explained by the effect of macrophage function.…”

Section: Discussionmentioning

confidence: 61%

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Macrophages Promote Osteoblastic Differentiation In Vivo: Implications in Fracture Repair and Bone Homeostasis

Baht

Whetstone

et al. 2014

Journal of Bone and Mineral Research

254

257

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Macrophages are activated in inflammation and during early phases of repair processes. Interestingly, they are also present in bone during development, but their function during this process is unclear. Here, we explore the function of macrophages in bone development, growth, and repair using transgenic mice to constitutively or conditionally deplete macrophages. Depletion of macrophages led to early skeletal growth retardation and progressive osteoporosis. By 3 months of age, macrophage-deficient mice displayed a 25% reduction in bone mineral density and a 70% reduction in the number of trabecular bone compared to control littermates. Despite depletion of macrophages, functional osteoclasts were still present in bones, lining trabecular bone and the endosteal surface of the cortical bone. Furthermore, ablation of macrophages led to a 60% reduction in the number of bone marrow mesenchymal progenitor cells and a decrease in the ability of these cells to differentiate to osteoblasts. When macrophages were depleted during fracture repair, bone union was impaired. Calluses from macrophage-deficient animals were smaller, and contained less bone and more fibrotic tissue deposition. Taken together, this shows that macrophages are crucial for maintaining bone homeostasis and promoting fracture repair by enhancing the differentiation of mesenchymal progenitors.

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Section: Discussioncontrasting

confidence: 50%

Section: Discussionmentioning

confidence: 61%

Macrophages Promote Osteoblastic Differentiation In Vivo: Implications in Fracture Repair and Bone Homeostasis

Baht

Whetstone

et al. 2014

Journal of Bone and Mineral Research

254

257

View full text Add to dashboard Cite

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“…It has been demonstrated that T cells express RANKL and are capable of directly triggering osteoclastogenesis. In our previous article, we revealed T cell contribution in osteoclastogenesis in GD chemical model [21]. Moreover, T cells are the ones from the mix of mononuclear cells shown to induce spontaneous osteoclastogenesis when cultured with monocytes [32,6].…”

Section: Discussionmentioning

confidence: 95%

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

Mucci

Cuello

Kisinovsky³

et al. 2015

Blood Cells, Molecules, and Diseases

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“…Bone events are the most debilitating and disabling complication of GD. With substrate overload, Gaucher cells activate and induce proinflammatory cytokine synthesis which can modify the activity of the osteoblast-osteoclast system and promote lytic phenomena and intraosseous vascular complications [34,35]. Further analysis of the interaction between biomarkers and bone events is needed.…”

Section: Discussionmentioning

confidence: 99%

Modeling changes in biomarkers in Gaucher disease patients receiving enzyme replacement therapy using a pathophysiological model

Vigan

Stirnemann

Caillaud

et al. 2014

Orphanet Journal of Rare Diseases

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BackgroundGaucher disease (GD) is a rare recessively inherited disorder caused by deficiency of a lysosomal enzyme, glucocerebrosidase. Accumulation of glucosylceramide or glucosylsphingosine in macrophages leads to increased production of ferritin and chitotriosidase and to decreases in hemoglobin concentration and platelet count, which are used as blood biomarkers. GD is treated by enzyme replacement therapy (ERT) or, sometimes by substrate reduction therapy. However, no physiological model for analysis of biomarkers change during ERT has been proposed. We aimed to develop a pathophysiological model to analyze biomarker’s response to ERT and several covariates impact.MethodsChanges in blood ferritin, chitotriosidase, hemoglobin and platelets were analyzed in French GD Registry patients receiving imiglucerase/alglucerase as ERT. We used simplified exponential pathophysiological model, with initial concentration, biomarkers amplitude of variation and rate constant of normalization during ERT. Changes in four biomarkers were analyzed separately and then all four together from initiation to discontinuation of ERT, or until the end of follow-up. Several covariates were tested, including age at ERT initiation, splenectomy, sex, genotype (N370S/N370S), and ERT dose.ResultsAn exponential model gave a good data fit. The four biomarkers analysis showed that the rate of nomalization was the same for all biomarkers, with a half-life of 0.5 years. Predicted values of biomarkers at ERT’s steady state were 40% and 10% of initial concentrations, for ferritin and chitotriosidase, respectively, and 120% and 200% for hemoglobin and platelets, respectively. We found that 3 covariates had an effect on initial concentration or on amplitude of variation in ferritin, hemoglobin and platelets: women and patients under 15 years of age had lower ferritin and hemoglobin concentrations, and patients under 15 years of age had higher platelet count. Splenectomized patients had higher ferritin concentrations and platelet count and lower amplitude of variation of hemoglobin.ConclusionWe report the first dynamic model of biomarker changes in GD. It enabled us to estimate that 95% of biomarker response to ERT was achieved in 2 years, but with high inter-patient variability. We also found that with the current treatment, normalization of chitotriosidase and ferritin will occur in about 65% of patients.

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Uncoupling of osteoblast–osteoclast regulation in a chemical murine model of Gaucher disease

Cited by 22 publications

References 10 publications

Macrophages Promote Osteoblastic Differentiation In Vivo: Implications in Fracture Repair and Bone Homeostasis

Macrophages Promote Osteoblastic Differentiation In Vivo: Implications in Fracture Repair and Bone Homeostasis

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

Modeling changes in biomarkers in Gaucher disease patients receiving enzyme replacement therapy using a pathophysiological model

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