Constitutive activation of MEK1 in osteoprogenitors increases strength of bone despite impairing mineralization

John L. Fowlkes, R. Clay Bunn, Philip D. Ray, Evangelia Kalaitzoglou, Sasidhar Uppuganti, Mustafa Unal, Jeffry S. Nyman, Kathryn M. Thrailkill

Research output: Contribution to journalArticlepeer-review

4 Scopus citations

Abstract

Recent clinical studies have revealed that a somatic mutation in MAP2K1, causing constitutive activation of MEK1 in osteogenic cells, occurs in melorheostotic bone disease in humans. We have generated a mouse model which expresses an activated form of MEK1 (MEK1DD) specifically in osteoprogenitors postnatally. The skeletal phenotype of these mice recapitulates many features of melorheostosis observed in humans, including extra-cortical bone formation, abundant osteoid formation, decreased mineral density, and increased porosity. Paradoxically, in both humans and mice, MEK1 activation in osteoprogenitors results in bone that is not structurally compromised, but is hardened and stronger, which would not be predicted based on tissue and matrix properties. Thus, a specific activating mutation in MEK1, expressed only by osteoprogenitors postnatally, can have a significant impact on bone strength through complex alterations in whole bone geometry, bone micro-structure, and bone matrix.

Original languageEnglish
Article number115106
JournalBone
Volume130
DOIs
StatePublished - Jan 2020

Bibliographical note

Funding Information:
This work was supported by grants from the National Institutes of Health , R56DK055653 (to J.L.F.), R21AR070620 (to K.M.T and J.S.N), and R21AR072483 (to J.S.N.); as well as funding from University of Kentucky Barnstable Brown Diabetes Center Research Endowments . Appendix A

Publisher Copyright:
© 2019 Elsevier Inc.

Keywords

  • Bone strength
  • Bone structure
  • MEK1
  • Melorheostosis
  • Mitogen-activated protein kinase kinase 1 (MAP2K1)
  • Osteoid
  • Osteoprogenitor
  • Raman spectroscopy

ASJC Scopus subject areas

  • Endocrinology, Diabetes and Metabolism
  • Histology
  • Physiology

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