A molecular basis for neurofibroma-associated skeletal manifestations in NF1
| العنوان: | A molecular basis for neurofibroma-associated skeletal manifestations in NF1 |
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| المؤلفون: | Steven P. Angus, Kwangmin Choi, Noah Sciaky, Katherine E. Chaney, Alexander Pemov, Florent Elefteriou, Andrea M. Gross, Jonathan J. Rios, Nancy Ratner, Steven D. Rhodes, Eva Dombi, Brigitte C. Widemann, D. Wade Clapp, Yun Ma |
| المصدر: | Genetics in medicine : official journal of the American College of Medical Genetics |
| سنة النشر: | 2020 |
| مصطلحات موضوعية: | pyrophosphate, Neurofibromatosis 1, Schwann cell, Article, Neurofibromatosis, Mice, Plexiform neurofibroma, Medicine, Neurofibroma, Animals, Humans, Protein Kinase Inhibitors, Genetics (clinical), Bone mineral, Neurofibroma, Plexiform, MEK inhibitor, business.industry, medicine.disease, medicine.anatomical_structure, bone mineralization, neurofibromas, Selumetinib, Cancer research, Schwann Cells, business, Homeostasis |
| الوصف: | Purpose Plexiform neurofibromas (NF) develop in children with Neurofibromatosis Type 1 (NF1) and can be associated with several skeletal co-morbidities. Preclinical mouse studies revealed Nf1 deficiency in osteoprogenitor cells disrupts, in a MEK-dependent manner, pyrophosphate (PPi) homeostasis and skeletal mineralization. The etiology of NF-associated skeletal manifestations remains unknown. Methods We used mouse models of NF1 neurofibromas to assess bone mineralization of skeletal structures adjacent to tumors. Expression of genes involved in pyrophosphate homeostasis was assessed in mouse and human NF tumors and Schwann cell cultures. We used Dual-energy X-ray Absorptiometry (DXA) to assess tumor-associated changes in bone mineral density (BMD) in an individual with NF1 following treatment with the MEK inhibitor selumetinib. Results We detected increased non-mineralized bone surfaces adjacent to tumors in mouse models of NF1 neurofibromas. Expression of Enpp1, a PPi-generating ectophosphatase, and ANKH, a PPi transporter, was increased in mouse and human neurofibroma-derived tissues and Schwann cells, respectively. In one patient, tumor-associated reductions in BMD were partially rescued following therapy with selumetinib. Conclusion Results indicate that NF-associated skeletal pathologies in NF1 are associated with dysregulated pyrophosphate homeostasis in adjacent NF tumors and suggest that treatment of NFs with MEK inhibitors may improve skeletal manifestations of the disease. |
| اللغة: | English |
| تدمد: | 1530-0366 1098-3600 |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::1403bc987c36b76af61da93fddb7baccTest http://europepmc.org/articles/PMC8106869Test |
| حقوق: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....1403bc987c36b76af61da93fddb7bacc |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 15300366 10983600 |
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