MEK-SHP2 inhibition prevents tibial pseudarthrosis caused by <i>NF1</i> loss in Schwann cells and skeletal stem/progenitor cells.

ABSTRACT: Congenital pseudarthrosis of the tibia (CPT) is a severe pathology marked by spontaneous bone fractures that fail to heal, leading to fibrous nonunion. Half of patients with CPT are affected by the multisystemic genetic disorder neurofibromatosis type 1 (NF1) caused by mutations in the NF1 tumor suppressor gene, a negative regulator of RAS-mitogen-activated protein kinase (MAPK) signaling pathway. Here, we analyzed patients with CPT and Prss56-Nf1 knockout mice to elucidate the pathogenic mechanisms of CPT-related fibrous nonunion and explored a pharmacological approach to treat CPT. We identified NF1-deficient Schwann cells and skeletal stem/progenitor cells (SSPCs) in pathological periosteum as affected cell types driving fibrosis. Whereas NF1-deficient SSPCs

SUBMITTER: Perrin S 

PROVIDER: S-EPMC12093263 | biostudies-literature | 2024 Jun

REPOSITORIES: biostudies-literature