Neurofibromatosis type 1(NF1)is a genetic disorder affecting 1 in 3000 people due to heterozygous mutations in the NF1 gene.Patients with NF1 can develop multiple symptoms,such as neurofibromas,skin hyperpigmentation,...Neurofibromatosis type 1(NF1)is a genetic disorder affecting 1 in 3000 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.展开更多
Musculoskeletal traumatic injuries(MTI)involve soft tissue lesions adjacent to a bone fracture leading to fibrous nonunion.The impact of MTI on the inflammatory response to fracture and on the immunomodulation of skel...Musculoskeletal traumatic injuries(MTI)involve soft tissue lesions adjacent to a bone fracture leading to fibrous nonunion.The impact of MTI on the inflammatory response to fracture and on the immunomodulation of skeletal stem/progenitor cells(SSPCs)remains unknown.Here,we used single-nucleus transcriptomic analyses to describe the immune cell dynamics after bone fracture and identified distinct macrophage subsets with successive pro-inflammatory,pro-repair and anti-inflammatory profiles.Concurrently,SSPCs transition via a pro-and anti-inflammatory fibrogenic phase of differentiation prior to osteochondrogenic differentiation.In a preclinical MTI mouse model,the injury response of immune cells and SSPCs is disrupted leading to a prolonged pro-inflammatory phase and delayed resolution of inflammation.Macrophage depletion improves bone regeneration in MTI demonstrating macrophage involvement in fibrous nonunion.Finally,pharmacological inhibition of macrophages using the CSF1R inhibitor Pexidartinib ameliorates healing.These findings reveal the coordinated immune response of macrophages and skeletal stem/progenitor cells as a driver of bone healing and as a primary target for the treatment of trauma-associated fibrosis.展开更多
基金Association Neurofibromatoses et Recklinghausen(C.C)Agence Nationale de la Recherche-18-CE14-0033(C.C.,P.T.)+2 种基金Agence Nationale de la Recherche-21-CE18-007-01(C.C.,P.T.)US Department of the Army NF220019(C.C.)supported by a PhD fellowship from the University Paris-Est Créteil and the Fondation pour la Recherche Médicale(FRM)(FDT202304016600 to FK and ECO202306017399 to CG)。
文摘Neurofibromatosis type 1(NF1)is a genetic disorder affecting 1 in 3000 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.
基金supported by National Institute of Arthritis and Musculoskeletal and Skin Diseases R01 AR072707 (C.C.and Ted Miclau)and R01 AR081671 (C.C.and Ralph Marcucio)Agence Nationale de la Recherche ANR-18-CE14-0033 and ANR-21-CE18-007-01 (C.C.)。
文摘Musculoskeletal traumatic injuries(MTI)involve soft tissue lesions adjacent to a bone fracture leading to fibrous nonunion.The impact of MTI on the inflammatory response to fracture and on the immunomodulation of skeletal stem/progenitor cells(SSPCs)remains unknown.Here,we used single-nucleus transcriptomic analyses to describe the immune cell dynamics after bone fracture and identified distinct macrophage subsets with successive pro-inflammatory,pro-repair and anti-inflammatory profiles.Concurrently,SSPCs transition via a pro-and anti-inflammatory fibrogenic phase of differentiation prior to osteochondrogenic differentiation.In a preclinical MTI mouse model,the injury response of immune cells and SSPCs is disrupted leading to a prolonged pro-inflammatory phase and delayed resolution of inflammation.Macrophage depletion improves bone regeneration in MTI demonstrating macrophage involvement in fibrous nonunion.Finally,pharmacological inhibition of macrophages using the CSF1R inhibitor Pexidartinib ameliorates healing.These findings reveal the coordinated immune response of macrophages and skeletal stem/progenitor cells as a driver of bone healing and as a primary target for the treatment of trauma-associated fibrosis.
