PIN1 Attenuation Improves Midface Hypoplasia in a Mouse Model of Apert Syndrome

Abstract

Premature fusion of the cranial suture and midface hypoplasia are common features of syndromic craniosynostosis caused by mutations in the FGFR2 gene. The only treatment for this condition involves a series of risky surgical procedures designed to correct defects in the craniofacial bones, which must be performed until brain growth has been completed. Several pharmacologic interventions directed at FGFR2 downstream signaling have been tested as potential treatments for premature coronal suture fusion in a mouse model of Apert syndrome. However, there are no published studies that have targeted for the pharmacologic treatment of midface hypoplasia. We used Fgfr2S252W/+ knock-in mice as a model of Apert syndrome and morphometric analyses to identify causal hypoplastic sites in the midface region. Three-dimensional geometric and linear analyses of Fgfr2S252W/+ mice at postnatal day 0 demonstrated distinct morphologic variance. The premature fusion of anterior facial bones, such as the maxilla, nasal, and frontal bones, rather than the cranium or cranial base, is the main contributing factor toward the anterior-posterior skull length shortening. The cranial base of the mouse model had a noticeable downward slant around the intersphenoid synchondrosis, which is related to distortion of the airway. Within a skull, the facial shape variance was highly correlated with the cranial base angle change along Fgfr2 S252W mutation–induced craniofacial anomalies. The inhibition of an FGFR2 downstream signaling enzyme, PIN1, via genetic knockdown or use of a PIN1 inhibitor, juglone, attenuated the aforementioned deformities in a mouse model of Apert syndrome. Overall, these results indicate that FGFR2 signaling is a key contributor toward abnormal anterior-posterior dimensional growth in the midface region. Our study suggests a novel therapeutic option for the prevention of craniofacial malformations induced by mutations in the FGFR2 gene.

RUNX2-modifying enzymes: therapeutic targets for bone diseases

“…Enhanced RUNX2 acetylation by HDIs 57 and direct PIN1 delivery 63 may upregulate RUNX2 activity to rescue genetic RUNX2 deficiency in CCD. FGFR2 receptor tyrosine kinase inhibitors [41][42][43] , downstream ERK inhibitors 36 or PIN1 inhibitors 29,30 can rescue FGFR2-hyperactivating mutations in CS. Previous results also suggest that a genetic disease caused by a single gene mutation can be overcome by regulation of the molecular metabolism associated with the causative protein.…”

“…The cis-trans isomerization mediated by PIN1 can be blocked by well-known inhibitors such as juglone 46 and DTM 47 . Intraperitoneal administration of juglone to pregnant Fgfr2 S252W mice from E14.5 to E18.5 was found to successfully interrupt fetal development of Apert syndrome phenotypes, including early suture closure 29 and midfacial deformalities 30 . Additionally, the expression levels of the FGFR2 downstream genes Dusp6, Spry2, and Spry3 are attenuated by juglone treatment in primary cultured osteoblasts from Fgfr2 S252W mice 29,30 .…”

“…Intraperitoneal administration of juglone to pregnant Fgfr2 S252W mice from E14.5 to E18.5 was found to successfully interrupt fetal development of Apert syndrome phenotypes, including early suture closure 29 and midfacial deformalities 30 . Additionally, the expression levels of the FGFR2 downstream genes Dusp6, Spry2, and Spry3 are attenuated by juglone treatment in primary cultured osteoblasts from Fgfr2 S252W mice 29,30 . Posttranslational stabilization and activation of RUNX2 in Fgfr2 S252W osteoblasts are also attenuated by PIN1 inhibition 29 .…”

“…CS which is defined as the premature fusion of one or more of the cranial sutures, presents as secondary distortion of the skull 29 and midfacial hypoplastic changes 30 that occur because of the combination of a lack of growth perpendicular to the fused sutures, compensatory overgrowth at the nonfused sutures, and structural interrelation between cranial bony components 31 . Most genetically determined CS is characterized by autosomal dominant inheritance, and the genes most commonly mutated in CS are FGFR2, FGFR3, TWIST1, and EFNB1 32 .…”

Airway Development Relevant to Cranial Vault Suture Synostosis Subtype in Apert Syndrome

“…All are related to disturbances in the airway. 40 Although this study is limited by the variation in age distribution between the 3 subtypes, this uneven ratio reflects the actual incidence in each kind of cranial vault suture synostosis (Type I. Bilateral coronal synostosis; type II.…”