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Gingival proteomics reveals the role of TGF beta and YAP/TAZ signaling in Raine syndrome fibrosis.
Costa, Cláudio Rodrigues Rezende; Chalgoumi, Rym; Baker, Amina; Guillou, Clément; Yamaguti, Paulo Marcio; Simancas Escorcia, Victor; Abbad, Lilia; Amorin, Bruna Rabelo; de Lima, Caroline Lourenço; Cannaya, Vidjea; Benassarou, Mourad; Berdal, Ariane; Chatziantoniou, Christos; Cases, Olivier; Cosette, Pascal; Kozyraki, Renata; Acevedo, Ana Carolina.
Afiliación
  • Costa CRR; Centre de Recherche des Cordeliers, Sorbonne Université, INSERM, Université de Paris Cité, Oral Molecular Pathophysiology, 75006, Paris, France.
  • Chalgoumi R; Oral Center for Inherited Diseases, University Hospital of Brasília, Oral Histopathology Laboratory, Department of Dentistry, Health Sciences Faculty, University of Brasília (UnB), Brasília, Brazil.
  • Baker A; Department of Dentistry, Health Group of Natal (GSAU-NT), Brazilian Air Force, Natal, Parnamirim, Brazil.
  • Guillou C; Centre de Recherche des Cordeliers, Sorbonne Université, INSERM, Université de Paris Cité, Oral Molecular Pathophysiology, 75006, Paris, France.
  • Yamaguti PM; Centre de Recherche des Cordeliers, Sorbonne Université, INSERM, Université de Paris Cité, Oral Molecular Pathophysiology, 75006, Paris, France.
  • Simancas Escorcia V; Rouen University, INSA Rouen Normandie, CNRS, Normandie Univ, PBS UMR 6270, 76000, Rouen, France.
  • Abbad L; Rouen University, INSERM US51, CNRS UAR 2026, HeRacles PISSARO, 76000, Rouen, France.
  • Amorin BR; Oral Center for Inherited Diseases, University Hospital of Brasília, Oral Histopathology Laboratory, Department of Dentistry, Health Sciences Faculty, University of Brasília (UnB), Brasília, Brazil.
  • de Lima CL; Centre de Recherche des Cordeliers, Sorbonne Université, INSERM, Université de Paris Cité, Oral Molecular Pathophysiology, 75006, Paris, France.
  • Cannaya V; Grupo de Investigación GENOMA, Universidad del Sinú, Cartagena, Colombia.
  • Benassarou M; MRS1155, INSERM, Sorbonne Université, 75020, Paris, France.
  • Berdal A; Oral Center for Inherited Diseases, University Hospital of Brasília, Oral Histopathology Laboratory, Department of Dentistry, Health Sciences Faculty, University of Brasília (UnB), Brasília, Brazil.
  • Chatziantoniou C; Oral Center for Inherited Diseases, University Hospital of Brasília, Oral Histopathology Laboratory, Department of Dentistry, Health Sciences Faculty, University of Brasília (UnB), Brasília, Brazil.
  • Cases O; Centre de Recherche des Cordeliers, Sorbonne Université, INSERM, Université de Paris Cité, Oral Molecular Pathophysiology, 75006, Paris, France.
  • Cosette P; Service de Chirurgie Maxillo-Faciale et Stomatologie, Hôpital de La Pitié Salpétrière, Sorbonne Université, 75006, Paris, France.
  • Kozyraki R; Centre de Recherche des Cordeliers, Sorbonne Université, INSERM, Université de Paris Cité, Oral Molecular Pathophysiology, 75006, Paris, France.
  • Acevedo AC; CRMR O-RARES, Hôpital Rothshild, UFR d'Odontologie-Garancière, Université de Paris Cité, 75012, Paris, France.
Sci Rep ; 14(1): 9497, 2024 04 25.
Article en En | MEDLINE | ID: mdl-38664418
ABSTRACT
Raine syndrome (RNS) is a rare autosomal recessive osteosclerotic dysplasia. RNS is caused by loss-of-function disease-causative variants of the FAM20C gene that encodes a kinase that phosphorylates most of the secreted proteins found in the body fluids and extracellular matrix. The most common RNS clinical features are generalized osteosclerosis, facial dysmorphism, intracerebral calcifications and respiratory defects. In non-lethal RNS forms, oral traits include a well-studied hypoplastic amelogenesis imperfecta (AI) and a much less characterized gingival phenotype. We used immunomorphological, biochemical, and siRNA approaches to analyze gingival tissues and primary cultures of gingival fibroblasts of two unrelated, previously reported RNS patients. We showed that fibrosis, pathological gingival calcifications and increased expression of various profibrotic and pro-osteogenic proteins such as POSTN, SPARC and VIM were common findings. Proteomic analysis of differentially expressed proteins demonstrated that proteins involved in extracellular matrix (ECM) regulation and related to the TGFß/SMAD signaling pathway were increased. Functional analyses confirmed the upregulation of TGFß/SMAD signaling and subsequently uncovered the involvement of two closely related transcription cofactors important in fibrogenesis, Yes-associated protein (YAP) and transcriptional coactivator with PDZ-binding motif (TAZ). Knocking down of FAM20C confirmed the TGFß-YAP/TAZ interplay indicating that a profibrotic loop enabled gingival fibrosis in RNS patients. In summary, our in vivo and in vitro data provide a detailed description of the RNS gingival phenotype. They show that gingival fibrosis and calcifications are associated with, and most likely caused by excessed ECM production and disorganization. They furthermore uncover the contribution of increased TGFß-YAP/TAZ signaling in the pathogenesis of the gingival fibrosis.
Asunto(s)
Anomalías Múltiples; Proteínas Adaptadoras Transductoras de Señales; Fisura del Paladar; Hipoplasia del Esmalte Dental; Exoftalmia; Fibroblastos; Fibrosis; Encía; Osteosclerosis; Proteómica; Transducción de Señal; Factores de Transcripción; Factor de Crecimiento Transformador beta; Proteínas Señalizadoras YAP; Humanos; Factor de Crecimiento Transformador beta/metabolismo; Encía/metabolismo; Encía/patología; Proteómica/métodos; Fibrosis/metabolismo; Proteínas Señalizadoras YAP/metabolismo; Proteínas Señalizadoras YAP/genética; Osteosclerosis/metabolismo; Osteosclerosis/genética; Osteosclerosis/patología; Proteínas Adaptadoras Transductoras de Señales/metabolismo; Proteínas Adaptadoras Transductoras de Señales/genética; Factores de Transcripción/metabolismo; Factores de Transcripción/genética; Hipoplasia del Esmalte Dental/metabolismo; Hipoplasia del Esmalte Dental/genética; Hipoplasia del Esmalte Dental/patología; Fibroblastos/metabolismo; Fibroblastos/patología; Microcefalia/metabolismo; Microcefalia/genética; Microcefalia/patología; Femenino; Proteínas Coactivadoras Transcripcionales con Motivo de Unión a PDZ/metabolismo; Masculino; Transactivadores/metabolismo; Transactivadores/genética; Péptidos y Proteínas de Señalización Intracelular/metabolismo; Péptidos y Proteínas de Señalización Intracelular/genética; Quinasa de la Caseína I/metabolismo; Quinasa de la Caseína I/genética; Proteínas de la Matriz Extracelular/metabolismo; Proteínas de la Matriz Extracelular/genética; Amelogénesis Imperfecta/metabolismo; Amelogénesis Imperfecta/genética; Amelogénesis Imperfecta/patología; Células Cultivadas
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Osteosclerosis / Factores de Transcripción / Anomalías Múltiples / Fibrosis / Transducción de Señal / Exoftalmia / Factor de Crecimiento Transformador beta / Fisura del Paladar / Hipoplasia del Esmalte Dental / Proteómica Idioma: En Revista: Sci Rep Año: 2024 Tipo del documento: Article País de afiliación: Francia Pais de publicación: Reino Unido
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Osteosclerosis / Factores de Transcripción / Anomalías Múltiples / Fibrosis / Transducción de Señal / Exoftalmia / Factor de Crecimiento Transformador beta / Fisura del Paladar / Hipoplasia del Esmalte Dental / Proteómica Idioma: En Revista: Sci Rep Año: 2024 Tipo del documento: Article País de afiliación: Francia Pais de publicación: Reino Unido