Asfotase-α improves bone growth, mineralization and strength in mouse models of neurofibromatosis type-1

Ndong, Jean De La Croix; Makowski, Alexander J.; Uppuganti, Sasidhar; Vignaux, Guillaume; Ono, Kazuhisa; Perrien, Daniel S.; Joubert, Simon; Baglio, S. Rubina; Granchi, Donatella; Stevenson, David A.; Rios, Jonathan J.; Nyman, Jeffry S.; Elefteriou, Florent

doi:10.1038/nm.3583

Cited by 56 publications

(62 citation statements)

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“…However, the origin of these proliferative cells is still unknown. These results are also consistent with the defect of differentiation observed in Nf1 deficient osteoprogenitors,15 which may explain why the mutation is found in proliferative cells and not within cortical bone tissue, as the latter by definition contains mostly mature differentiated osteoblasts and osteocytes.…”

Section: Discussionsupporting

confidence: 84%

“…It is postulated that bi-allelic inactivation of the NF1 locus is necessary for the development of pseudarthrosis in NF1 and this has been documented in several instances in human biopsies,9 10 12–14 and further supported by the phenotype of mouse models characterised by biallelic Nf1 loss of function in osteoprogenitors 15. However, the tissue or cell of origin of the ‘second hit’ mutation in human individuals remains unclear.…”

Section: Introductionmentioning

confidence: 99%

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Evaluation of somatic mutations in tibial pseudarthrosis samples in neurofibromatosis type 1

et al. 2015

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Background Tibial pseudarthrosis is associated with neurofibromatosis type 1 (NF1) and there is wide clinical variability of the tibial dysplasia in NF1, suggesting the possibility of genetic modifiers. Double inactivation of NF1 is postulated to be necessary for the development of tibial pseudarthrosis, but tissue or cell of origin of the ‘second hit’ mutation remains unclear. Methods Exome sequencing of different sections of surgically resected NF1 tibial pseudarthrosis tissue was performed and compared to germline (peripheral blood). Results A germline NF1 splice site mutation (c.61-2A>T, p.L21 M68del) was identified from DNA extracted from peripheral blood. Exome sequencing of DNA extracted from tissue removed during surgery of the tibial pseudarthrosis showed a somatic mutation of NF1 (c.3574G>T, p.E1192*) in the normal germline allele. Further analysis of different regions of the tibial pseudarthrosis sample showed enrichment of the somatic mutation in the soft tissue within the pseudarthrosis site and absence of the somatic mutation in cortical bone. In addition, a germline variant in PTPN11 (c.1658C>T, p.T553M), a gene involved in the RAS signal transduction pathway was identified, although the clinical significance is unknown. Conclusions Given that the NF1 somatic mutation was primarily detected in the proliferative soft tissue at the pseudarthrosis site, it is likely that the second hit occurred in mesenchymal progenitors from the periosteum. These results are consistent with a defect of differentiation, which may explain why the mutation is found in proliferative cells and not within cortical bone tissue, as the latter by definition contains mostly mature differentiated osteoblasts and osteocytes.

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Section: Discussionsupporting

confidence: 84%

Section: Introductionmentioning

confidence: 99%

Evaluation of somatic mutations in tibial pseudarthrosis samples in neurofibromatosis type 1

et al. 2015

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“…BMCs were differentiated to osteoblasts using 50 μg/mL ascorbic acid and 5 mmol β-glycerophosphate (Sigma-Aldrich, St. Louis, MO) (11). Osteoblasts were cultured with 100 ng/mL recombinant murine granulocyte colony-stimulating factor (G-CSF) (R&D Systems), 50 μg/mL anti-CD45RB (BioXCell, West Lebanon, NH), or media alone (control) for 24 h. Cells were analyzed by flow cytometry or RT-PCR (primers described in Supplementary Fig.…”

Section: Methodsmentioning

confidence: 99%

Hematopoietic Stem Cell Mobilization Is Necessary but Not Sufficient for Tolerance in Islet Transplantation

et al. 2016

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Overcoming the immune response to establish durable immune tolerance in type 1 diabetes remains a substantial challenge. The ongoing effector immune response involves numerous immune cell types but is ultimately orchestrated and sustained by the hematopoietic stem cell (HSC) niche. We therefore hypothesized that tolerance induction also requires these pluripotent precursors. In this study, we determined that the tolerance-inducing agent anti-CD45RB induces HSC mobilization in nonautoimmune B6 mice but not in diabetes-prone NOD mice. Ablation of HSCs impaired tolerance to allogeneic islet transplants in B6 recipients. Mobilization of HSCs resulted in part from decreasing osteoblast expression of HSC retention factors. Furthermore, HSC mobilization required a functioning sympathetic nervous system; sympathectomy prevented HSC mobilization and completely abrogated tolerance induction. NOD HSCs were held in their niche by excess expression of CXCR4, which, when blocked, led to HSC mobilization and prolonged islet allograft survival. Overall, these findings indicate that the HSC compartment plays an underrecognized role in the establishment and maintenance of immune tolerance, and this role is disrupted in diabetes-prone NOD mice. Understanding the stem cell response to immune therapies in ongoing human clinical studies may help identify and maximize the effect of immune interventions for type 1 diabetes.

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“…He also presented preliminary results revealing reduced speed of sound utilizing quantitative ultrasound (QUS) in non-fractured bowed tibia compared to the contralateral side in 23 NF1 patients. As preclinical studies suggest the possibility to prevent changes in bone quality via enzyme therapy against pyrophosphate accumulation in children with NF1 (de la Croix Ndong et al, 2014), QUS may be an appropriate outcome measure to predict bone quality and identify patients to recruit in future clinical trials.…”

Section: Musculoskeletal Abnormalities In Nf1mentioning

confidence: 99%

2016 Children's Tumor Foundation conference on neurofibromatosis type 1, neurofibromatosis type 2, and schwannomatosis

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et al. 2018

American J of Med Genetics Pt A

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Organized and hosted by the Children's Tumor Foundation (CTF), the Neurofibromatosis (NF) conference is the premier annual gathering for clinicians and researchers interested in neurofibromatosis type 1 (NF1), neurofibromatosis type 2 (NF2), and schwannomatosis (SWN). The 2016 edition constituted a blend of clinical and basic aspects of NF research that helped in clarifying different advances in the field. The incorporation of next generation sequencing is changing the way genetic diagnostics is performed for NF and related disorders, providing solutions to problems like genetic heterogeneity, overlapping clinical manifestations, or the presence of mosaicism. The transformation from plexiform neurofibroma (PNF) to malignant peripheral nerve sheath tumor (MPNST) is being clarified, along with new management and treatments for benign and premalignant tumors. Promising new cellular and in vivo models for understanding the musculoskeletal abnormalities in NF1, the development of NF2 or SWN associated schwannomas, and clarifying the cells that give rise to NF1-associated optic pathway glioma were presented. The interaction of neurofibromin and SPRED1 was described comprehensively, providing functional insight that will help in the interpretation of pathogenicity of certain missense variants identified in NF1 and Legius syndrome patients. Novel promising imaging techniques are being developed, as well as new integrative and holistic management models for patients that take into account psychological, social, and biological factors. Importantly, new therapeutic approaches for schwannomas, meningiomas, ependymomas, PNF, and MPNST are being pursued. This report highlights the major advances that were presented at the 2016 CTF NF conference.

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Asfotase-α improves bone growth, mineralization and strength in mouse models of neurofibromatosis type-1

Cited by 56 publications

References 61 publications

Evaluation of somatic mutations in tibial pseudarthrosis samples in neurofibromatosis type 1

Evaluation of somatic mutations in tibial pseudarthrosis samples in neurofibromatosis type 1

Hematopoietic Stem Cell Mobilization Is Necessary but Not Sufficient for Tolerance in Islet Transplantation

2016 Children's Tumor Foundation conference on neurofibromatosis type 1, neurofibromatosis type 2, and schwannomatosis

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