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 <i>NF1</i> tumor suppressor gene, a negative regulator of RAS-mitogen-activated protein kinase (MAPK) signaling pathway. Here, we analyzed patients with CPT and <i>Prss56-Nf1</i> knockout mice to elucidate the pathogenic mechanisms of CPT-related fibrous nonunion and explored a pharmacological approach to treat CPT. We identified <i>NF1</i>-deficient Schwann cells and skeletal stem/progenitor cells (SSPCs) in pathological periosteum as affected cell types driving fibrosis. Whereas <i>NF1</i>-deficient SSPCs adopted a fibrotic fate, <i>NF1</i>-deficient Schwann cells produced critical paracrine factors including transforming growth factor-β and induced fibrotic differentiation of wild-type SSPCs. To counteract the elevated RAS-MAPK signaling in both <i>NF1</i>-deficient Schwann cells and SSPCs, we used MAPK kinase (MEK) and Src homology 2 containing protein tyrosine phosphatase 2 (SHP2) inhibitors. Combined MEK-SHP2 inhibition in vivo prevented fibrous nonunion in the <i>Prss56-Nf1</i> knockout mouse model, providing a promising therapeutic strategy for the treatment of fibrous nonunion in CPT.