A molecular basis for neurofibroma-associated skeletal manifestations in NF1

Abstract

Purpose

Plexiform neurofibromas (pNF) develop in children with neurofibromatosis type 1 (NF1) and can be associated with several skeletal comorbidities. 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 nonmineralized 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.

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Fig. 1: Plexiform neurofibroma-associated neurofibromatosis type 1 (NF1) skeletal manifestations.
Fig. 2: Osteoidosis and increased expression of pyrophosphate (PPi)-related genes associated with murine neurofibromas.
Fig. 3: Activation of genes regulating pyrophosphate (PPi) in human plexiform neurofibromas (NFs).
Fig. 4: Case presentation of improved tumor-associated bone mineral density (BMD) following MEKi therapy.

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Acknowledgements

The authors thank Gerard Portela, Mark Ahlman, John Shern, Stuart Almond, B. Stephens Richards, and Molly Dempsey for their help with different aspects of this work. Research reported in this publication was supported by the Department of Defense (NF140019, F.E.), the Texas Neurofibromatosis Foundation (J.J.R), and Texas Scottish Rite Hospital for Children (J.J.R.). F.E. (R21-AR072483, R01-AG055394), N.R. (R01-NS28840), J.J.R and D.W.C. (U54-CA196519-04), and S.D.R. (K12-HD000850) were supported by funding from the National Institutes of Health. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

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Correspondence to Jonathan J. Rios PhD or Florent Elefteriou PhD.

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F.E. received research funding from Alexion (not related to this paper). The other authors declare no conflicts of interest.

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Ma, Y., Gross, A.M., Dombi, E. et al. A molecular basis for neurofibroma-associated skeletal manifestations in NF1. Genet Med (2020). https://doi.org/10.1038/s41436-020-0885-3

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Keywords

  • neurofibromatosis
  • neurofibromas
  • bone mineralization
  • pyrophosphate
  • MEK inhibitor