| Autor: |
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 |
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| Zdroj: |
Science Translational Medicine; 6/26/2024, Vol. 16 Issue 753, p1-13, 13p |
| Abstrakt: |
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 [ABSTRACT FROM AUTHOR] |
| Databáze: |
Complementary Index |
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