%0 Journal Article
%T MEK-SHP2 inhibition prevents tibial pseudarthrosis caused by NF1 loss in Schwann cells and skeletal stem/progenitor cells.
%A Perrin S
%A Protic S
%A Bretegnier V
%A Laurendeau I
%A de Lageneste OD
%A Panara N
%A Ruckebusch O
%A Luka M
%A Masson C
%A Maillard T
%A Coulpier F
%A Pannier S
%A Wicart P
%A Hadj-Rabia S
%A Radomska KJ
%A Zarhrate M
%A Ménager M
%A Vidaud D
%A Topilko P
%A Parfait B
%A Colnot C
%J Sci Transl Med
%V 16
%N 753
%D 2024 Jun 26
%M 38924432
%F 19.319
%R 10.1126/scitranslmed.adj1597
%X 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 adopted a fibrotic fate, NF1-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 NF1-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 Prss56-Nf1 knockout mouse model, providing a promising therapeutic strategy for the treatment of fibrous nonunion in CPT.