Pharmacological inhibition of RAS pathway alleviates spine deformity in a mouse model of neurofibromatosis type 1

Neurofibromatosis type 1 (NF1) is a genetic disorder affecting 1 in 3 000 people due to heterozygous mutations in the NF1 gene. Patients with NF1 can develop multiple symptoms, such as neurofibromas, skin hyperpigmentation, and bone abnormalities, including tibial pseudarthrosis and spine deformity. Here, we aimed to elucidate the cellular origin and pathogenic mechanism of NF1 spine deformity. We explored the Prss56-Nf1 knockout (KO) mouse model that recapitulates neurofibromas and pseudarthrosis by carrying Nf1 gene inactivation in Prss56-expressing boundary cap cells, a neural crest subset, and their derivatives. Micro-CT analyses showed that Prss56-Nf1 KO mice exhibit spine deformity from 12 months of age, associated with vertebral anomalies reminiscent of patients with NF1. Fate mapping revealed a significant increase in OSX⁺ osteoblasts of the Prss56 lineage in vertebrae of Prss56-Nf1 KO mice. Increased traced Nf1-deficient cells correlated with increased vertebral bone volume and kyphosis spine curvature. Finally, we showed that treating Prss56-Nf1 KO mice with RAS-MAPK pathway inhibitors prevented spine deformity. Overall, the Prss56-Nf1 KO mouse model unravels the role of osteoblasts from the Prss56 lineage as the cellular origin of NF1 spine deformity and highlights RAS-MAPK pathway inhibition as a promising therapeutic strategy for preventing NF1 spine deformity.