RESUMEN
Gain-of-function mutations in fibroblast growth factor receptors (FGFRs) cause congenital skeletal anomalies, including craniosynostosis (CS), which is characterized by the premature closure of craniofacial sutures. Apert syndrome (AS) is one of the severest forms of CS, and the only treatment is surgical expansion of prematurely fused sutures in infants. Previously, we demonstrated that the prolyl isomerase peptidyl-prolyl cis-trans isomerase interacting 1 (PIN1) plays a critical role in mediating FGFR signaling and that Pin1+/- mice exhibit delayed closure of cranial sutures. In this study, using both genetic and pharmacological approaches, we tested whether PIN1 modulation could be used as a therapeutic regimen against AS. In the genetic approach, we crossbred Fgfr2S252W/+, a mouse model of AS, and Pin1+/- mice. Downregulation of Pin1 gene dosage attenuated premature cranial suture closure and other phenotypes of AS in Fgfr2S252W/+ mutant mice. In the pharmacological approach, we intraperitoneally administered juglone, a PIN1 enzyme inhibitor, to pregnant Fgfr2S252W/+ mutant mice and found that this treatment successfully interrupted fetal development of AS phenotypes. Primary cultured osteoblasts from Fgfr2S252W/+ mutant mice expressed high levels of FGFR2 downstream target genes, but this phenotype was attenuated by PIN1 inhibition. Post-translational stabilization and activation of Runt-related transcription factor 2 (RUNX2) in Fgfr2S252W/+ osteoblasts were also attenuated by PIN1 inhibition. Based on these observations, we conclude that PIN1 enzyme activity is important for FGFR2-induced RUNX2 activation and craniofacial suture morphogenesis. Moreover, these findings highlight that juglone or other PIN1 inhibitors represent viable alternatives to surgical intervention for treatment of CS and other hyperostotic diseases.
Asunto(s)
Acrocefalosindactilia/genética , Subunidad alfa 1 del Factor de Unión al Sitio Principal/genética , Craneosinostosis/genética , Peptidilprolil Isomerasa de Interacción con NIMA/genética , Receptor Tipo 2 de Factor de Crecimiento de Fibroblastos/genética , Acrocefalosindactilia/tratamiento farmacológico , Acrocefalosindactilia/fisiopatología , Animales , Suturas Craneales/fisiopatología , Craneosinostosis/tratamiento farmacológico , Craneosinostosis/fisiopatología , Modelos Animales de Enfermedad , Femenino , Mutación con Ganancia de Función/genética , Regulación de la Expresión Génica/efectos de los fármacos , Humanos , Ratones , Morfogénesis , Peptidilprolil Isomerasa de Interacción con NIMA/antagonistas & inhibidores , Naftoquinonas/administración & dosificación , Osteoblastos/efectos de los fármacos , Osteoblastos/metabolismo , Embarazo , Cultivo Primario de Células , Transducción de SeñalAsunto(s)
Antineoplásicos/uso terapéutico , Anomalías Congénitas/tratamiento farmacológico , Acrocefalosindactilia/tratamiento farmacológico , Acrocefalosindactilia/enzimología , Acrocefalosindactilia/genética , Animales , Antineoplásicos/farmacología , Anomalías Congénitas/enzimología , Anomalías Congénitas/genética , Modelos Animales de Enfermedad , Humanos , Ratones , Proteínas Quinasas Activadas por Mitógenos/metabolismo , Modelos Biológicos , Transducción de Señal/efectos de los fármacos , Proteínas ras/metabolismoRESUMEN
Relapsing idiopathic nodular panniculitis is the term used to describe a group of diseases that presents as subcutaneous inflammatory nodules, fever and systemic symptoms and histopathologically displays inflammation within the fat lobules. There is no specific test for diagnosis and extensive investigations are required to exclude systemic causes of panniculitis. No uniform effective therapy is available and various drugs used include mainly corticosteroids alone or in combination with other immunosuppressive agents. Presented in this paper is an intractable case of idiopathic nodular panniculitis whose corticotherapy failed and could not be continued because of serious adverse effects. The rapid and good therapeutic response of the patient to mycophenolate mofetil monotherapy is discussed.