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


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.

SUBMITTER: Fowlkes JL 

PROVIDER: S-EPMC6914252 | biostudies-literature | 2020 Jan

REPOSITORIES: biostudies-literature

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

Fowlkes John L JL   Bunn R Clay RC   Ray Philip D PD   Kalaitzoglou Evangelia E   Uppuganti Sasidhar S   Unal Mustafa M   Nyman Jeffry S JS   Thrailkill Kathryn M KM  

Bone 20191102


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 minera  ...[more]

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