Section on Heritable Disorders of Bone and Extracellular Matrix, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, 20892, USA.
Clinical and Investigative Orthopedics Surgery Unit, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD, 20892, USA.
Nat Commun. 2018 Apr 11;9(1):1390. doi: 10.1038/s41467-018-03720-z.
Melorheostosis is a sporadic disease of uncertain etiology characterized by asymmetric bone overgrowth and functional impairment. Using whole exome sequencing, we identify somatic mosaic MAP2K1 mutations in affected, but not unaffected, bone of eight unrelated patients with melorheostosis. The activating mutations (Q56P, K57E and K57N) cluster tightly in the MEK1 negative regulatory domain. Affected bone displays a mosaic pattern of increased p-ERK1/2 in osteoblast immunohistochemistry. Osteoblasts cultured from affected bone comprise two populations with distinct p-ERK1/2 levels by flow cytometry, enhanced ERK1/2 activation, and increased cell proliferation. However, these MAP2K1 mutations inhibit BMP2-mediated osteoblast mineralization and differentiation in vitro, underlying the markedly increased osteoid detected in affected bone histology. Mosaicism is also detected in the skin overlying bone lesions in four of five patients tested. Our data show that the MAP2K1 oncogene is important in human bone formation and implicate MEK1 inhibition as a potential treatment avenue for melorheostosis.
骨肌皮病是一种病因不明的散发性疾病，其特征为不对称性骨过度生长和功能障碍。我们通过全外显子组测序，在 8 名无关联的骨肌皮病患者的受累而非未受累骨中发现了体细胞镶嵌 MAP2K1 突变。这些激活突变（Q56P、K57E 和 K57N）紧密聚集在 MEK1 的负调节域。受影响的骨骼在成骨细胞免疫组化中显示出 p-ERK1/2 增加的镶嵌模式。通过流式细胞术，从受累骨骼培养的成骨细胞包含两个具有不同 p-ERK1/2 水平的群体，ERK1/2 激活增强，细胞增殖增加。然而，这些 MAP2K1 突变抑制了 BMP2 介导的成骨细胞矿化和分化，这解释了在受累骨骼组织学中检测到的明显增加的类骨质。在检测的 5 名患者中的 4 名，在骨病变上方的皮肤中也检测到镶嵌现象。我们的数据表明，MAP2K1 癌基因在人类骨形成中很重要，并暗示 MEK1 抑制可能是治疗骨肌皮病的一种潜在途径。
