UMMS Affiliation

Division of Rheumatology, Department of Medicine

Publication Date

2020-11-11

Document Type

Article

Disciplines

Cell Biology | Congenital, Hereditary, and Neonatal Diseases and Abnormalities | Musculoskeletal Diseases | Nervous System Diseases

Abstract

Neurofibromatosis type I (NF1) is characterized by prominent skeletal manifestations caused by NF1 loss. While inhibitors of the ERK activating kinases MEK1/2 are promising as a means to treat NF1, the broad blockade of the ERK pathway produced by this strategy is potentially associated with therapy limiting toxicities. Here, we have sought targets offering a more narrow inhibition of ERK activation downstream of NF1 loss in the skeleton, finding that MEKK2 is a novel component of a noncanonical ERK pathway in osteoblasts that mediates aberrant ERK activation after NF1 loss. Accordingly, despite mice with conditional deletion of Nf1 in mature osteoblasts (Nf1(fl/fl);Dmp1-Cre) and Mekk2(-/-) each displaying skeletal defects, Nf1(fl/fl);Mekk2(-/-);Dmp1-Cre mice show an amelioration of NF1-associated phenotypes. We also provide proof-of-principle that FDA-approved inhibitors with activity against MEKK2 can ameliorate NF1 skeletal pathology. Thus, MEKK2 functions as a MAP3K in the ERK pathway in osteoblasts, offering a potential new therapeutic strategy for the treatment of NF1.

Keywords

Cell signalling, Bone, Peripheral nervous system, Diseases

Rights and Permissions

Copyright © The Author(s) 2020. Open Access. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

DOI of Published Version

10.1038/s41467-020-19555-6

Source

Bok S, Shin DY, Yallowitz AR, Eiseman M, Cung M, Xu R, Li N, Sun J, Williams AL, Scott JE, Su B, Shim JH, Greenblatt MB. MEKK2 mediates aberrant ERK activation in neurofibromatosis type I. Nat Commun. 2020 Nov 11;11(1):5704. doi: 10.1038/s41467-020-19555-6. PMID: 33177525; PMCID: PMC7658220. Link to article on publisher's site

Journal/Book/Conference Title

Nature communications

Related Resources

Link to Article in PubMed

PubMed ID

33177525

Creative Commons License

Creative Commons Attribution 4.0 License
This work is licensed under a Creative Commons Attribution 4.0 License.

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