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- Title
MEK-SHP2 inhibition prevents tibial pseudarthrosis caused by NF1 loss in Schwann cells and skeletal stem/progenitor cells.
- Authors
Perrin, Simon; Protic, Sanela; Bretegnier, Vincent; Laurendeau, Ingrid; de Lageneste, Oriane Duchamp; Panara, Nicolas; Ruckebusch, Odile; Luka, Marine; Masson, Cécile; Maillard, Théodora; Coulpier, Fanny; Pannier, Stéphanie; Wicart, Philippe; Hadj-Rabia, Smail; Radomska, Katarzyna J.; Zarhrate, Mohammed; Ménager, Mickael; Vidaud, Dominique; Topilko, Piotr; Parfait, Béatrice
- 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 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. Editor's summary: Congenital pseudarthrosis of the tibia (CPT) is a condition affecting children with bone fractures that fail to heal. CPT is often associated with the genetic disorder neurofibromatosis type 1 (NF1), which is caused by mutations in the gene of the same name. Perrin et al. examined how NF1 loss promotes this bone-healing phenotype in CPT. They report that NF1-deficient Schwann cells in the periosteum stimulate the differentiation of skeletal stem/progenitor cells into fibroblasts rather than chondrocytes as expected, which promotes fibrosis instead of bone formation. Combined treatment with MEK and SHP2 inhibitors prevented fibrotic failure to heal in a mouse model of NF1-CPT, suggesting a potential therapeutic strategy. —Catherine Charneski
- Subjects
SCHWANN cells; PROGENITOR cells; STEM cells; PSEUDARTHROSIS; BONE fractures in children; SPONTANEOUS fractures; BONE fractures; TERIPARATIDE; TRANSFORMING growth factors
- Publication
Science Translational Medicine, 2024, Vol 16, Issue 753, p1
- ISSN
1946-6234
- Publication type
Article
- DOI
10.1126/scitranslmed.adj1597