Metabolic dysfunction-associated steatotic liver disease(MASLD),formerly known as nonalcoholic fatty liver disease,is a chronic liver disease characterized by hepatic lipid deposition and hepatocellular steatosis,resu...Metabolic dysfunction-associated steatotic liver disease(MASLD),formerly known as nonalcoholic fatty liver disease,is a chronic liver disease characterized by hepatic lipid deposition and hepatocellular steatosis,resulting from nonalcoholic causes and closely linked to metabolic dysfunction[1].It is strongly associated with metabolic abnormalities,including type 2 diabetes,overweight,and obesity.The global prevalence of MASLD is estimated to be approximately 25%−33%,and its incidence is rising rapidly,particularly among younger populations,due to increasingly prevalent unhealthy lifestyle behaviors such as sleep deprivation,sedentary habits,and diets rich in calories.展开更多
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
文摘Metabolic dysfunction-associated steatotic liver disease(MASLD),formerly known as nonalcoholic fatty liver disease,is a chronic liver disease characterized by hepatic lipid deposition and hepatocellular steatosis,resulting from nonalcoholic causes and closely linked to metabolic dysfunction[1].It is strongly associated with metabolic abnormalities,including type 2 diabetes,overweight,and obesity.The global prevalence of MASLD is estimated to be approximately 25%−33%,and its incidence is rising rapidly,particularly among younger populations,due to increasingly prevalent unhealthy lifestyle behaviors such as sleep deprivation,sedentary habits,and diets rich in calories.
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.
