title: FGFR2 mutation confers a less drastic gain of function in mesenchymal stem cells than in fibroblasts.
abstract: Gain-of-function mutations in FGFR2 cause Apert syndrome (AS), a disease characterized by craniosynostosis and limb bone defects both due to abnormalities in bone differentiation and remodeling. Although the periosteum is an important cell source for bone remodeling, its role in craniosynostosis remains poorly characterized. We hypothesized that periosteal mesenchymal stem cells (MSCs) and fibroblasts from AS patients have abnormal cell phenotypes that contribute to the recurrent fusion of the coronal sutures. MSCs and fibroblasts were obtained from the periostea of 3 AS patients (S252W) and 3 control individuals (WT). We evaluated the proliferation, migration, and osteogenic differentiation of these cells. Interestingly, S252W mutation had opposite effects on different cell types: S252W MSCs proliferated less than WT MSCs, while S252W fibroblasts proliferated more than WT fibroblasts. Under restrictive media conditions, only S252W fibroblasts showed enhanced migration. The presence of S252W mutation increased in vitro and in vivo osteogenic differentiation in both studied cell types, though the difference compared to WT cells was more pronounced in S252W fibroblasts. This osteogenic differentiation was reversed through inhibition of JNK. We demonstrated that S252W fibroblasts can induce osteogenic differentiation in periosteal MSCs but not in MSCs from another tissue. MSCs and fibroblasts responded differently to the pathogenic effects of the FGFR2(S252W) mutation. We propose that cells from the periosteum have a more important role in the premature fusion of cranial sutures than previously thought and that molecules in JNK pathway are strong candidates for the treatment of AS patients.
authors: Human Genome Center, Department of Genetics and Evolutive Biology, Institute of Bioscience, University of Sao Paulo, Rua do Matão, 277, São Paulo, SP CEP 05508-900, Brazil.
authors: Erika
authors: E
authors: Yeh
authors: Rodrigo
authors: R
authors: Atique
authors: Felipe A A
authors: FA
authors: Ishiy
authors: Roberto Dalto
authors: RD
authors: Fanganiello
authors: Nivaldo
authors: N
authors: Alonso
authors: Hamilton
authors: H
authors: Matushita
authors: Katia Maria
authors: KM
authors: da Rocha
authors: Maria Rita
authors: MR
authors: Passos-Bueno
mesh_terms: D000168:Acrocephalosyndactylia / Q000235:genetics / Q000473:pathology; D000818:Animals; D000873:Anthracenes / Q000494:pharmacology; D015703:Antigens, CD / Q000378:metabolism; D001861:Bone Regeneration; D016022:Case-Control Studies; D002450:Cell Communication; D002454:Cell Differentiation; D002465:Cell Movement; D049109:Cell Proliferation; D005347:Fibroblasts / Q000378:metabolism* / Q000637:transplantation; D056726:Genetic Association Studies; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D008297:Male; D059630:Mesenchymal Stem Cells / Q000378:metabolism*; D020125:Mutation, Missense; D010012:Osteogenesis; D010521:Periosteum / Q000473:pathology; D010641:Phenotype; D051381:Rats; D017208:Rats, Wistar; D051497:Receptor, Fibroblast Growth Factor, Type 2 / Q000235:genetics*; D012886:Skull / Q000473:pathology / Q000503:physiopathology
chemical_list: D000873:Anthracenes; D015703:Antigens, CD; C432165:pyrazolanthrone; C496353:FGFR2 protein, human; D051497:Receptor, Fibroblast Growth Factor, Type 2; D048031:JNK Mitogen-Activated Protein Kinases