Fowlkes John L, Bunn R Clay, Ray Philip D, Kalaitzoglou Evangelia, Uppuganti Sasidhar, Unal Mustafa, Nyman Jeffry S, Thrailkill Kathryn M
University of Kentucky Barnstable Brown Diabetes Center, Lexington, KY, 40536, United States; Department of Pediatrics, University of Kentucky College of Medicine, Lexington, KY, 40536, United States.
University of Kentucky Barnstable Brown Diabetes Center, Lexington, KY, 40536, United States; Department of Pediatrics, University of Kentucky College of Medicine, Lexington, KY, 40536, United States.
Bone. 2020 Jan;130:115106. doi: 10.1016/j.bone.2019.115106. Epub 2019 Nov 2.
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.
近期临床研究表明，在人类骨肥大症中，MAP2K1发生体细胞突变，导致成骨细胞中的MEK1组成性激活。我们构建了一种小鼠模型，该模型在出生后特异性地在骨祖细胞中表达激活形式的MEK1（MEK1DD）。这些小鼠的骨骼表型概括了人类骨肥大症所观察到的许多特征，包括皮质外骨形成、大量类骨质形成、矿物质密度降低和孔隙率增加。矛盾的是，在人类和小鼠中，骨祖细胞中的MEK1激活都会导致骨骼在结构上未受损，但却变硬且更强壮，而这是根据组织和基质特性无法预测的。因此，仅在出生后由骨祖细胞表达的MEK1特异性激活突变，可通过对整个骨几何形状、骨微结构和骨基质的复杂改变，对骨强度产生重大影响。
