The effects of testosterone on craniosynostotic calvarial cells: a test of the gene/environmental model of craniofacial anomalies

Cray, JJ; Durham, EL; Smalley, MA; Finegold, David N.; Mj, Siegel; Losee, JE; Mp, Mooney; Cooper, Gregory

doi:10.1111/j.1601-6343.2011.01520.x

Cited by 6 publications

(8 citation statements)

References 37 publications

(62 reference statements)

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“…The aberrant proliferation of suture-derived cells that has been shown to contribute greatly to craniosynostosis [ 14 ], we then investigated the ability of periostin to modulate the proliferation of the suture-derived cells. As determined by CCK-8, a colorimetric assay used to measure cell viability and cytotoxicity, periostin significantly inhibited the proliferation of suture-derived cells in concentration- and time-dependent manners as compared with the non-treated group (Fig.…”

Section: Resultsmentioning

confidence: 99%

Recombinant mouse periostin ameliorates coronal sutures fusion in Twist1+/− mice

Bai

et al. 2018

J Transl Med

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BackgroundSaethre–Chotzen syndrome is an autosomal dominantly inherited disorder caused by mutations in the twist family basic helix-loop-helix transcription factor 1 (TWIST1) gene. Surgical procedures are frequently required to reduce morphological and functional defects in patients with Saethre–Chotzen syndrome. Therefore, the development of noninvasive procedures to treat Saethre–Chotzen syndrome is critical. We identified that periostin, which is an extracellular matrix protein that plays an important role in both bone and connective tissues, is downregulated in craniosynostosis patients.MethodsWe aimed to verify the effects of different concentrations (0, 50, 100, and 200 μg/l) of recombinant mouse periostin in Twist1+/− mice (a mouse model of Saethre–Chotzen syndrome) coronal suture cells in vitro and in vivo. Cell proliferation, migration, and osteogenic differentiation were observed and detected. Twist1+/− mice were also injected with recombinant mouse periostin to verify the treatment effects.ResultsCell Counting Kit-8 results showed that recombinant mouse periostin inhibited the proliferation of suture-derived cells in a time- and concentration-dependent manner. Cell migration was also suppressed when treated with recombinant mouse periostin. Real-time quantitative PCR and Western blotting results suggested that messenger ribonucleic acid and protein expression of alkaline phosphatase, bone sialoprotein, collagen type I, and osteocalcin were all downregulated after treatment with recombinant mouse periostin. However, the expression of Wnt-3a, Wnt-1, and β-catenin were upregulated. The in vivo results demonstrated that periostin-treated Twist1+/− mice showed patent coronal sutures in comparison with non-treated Twist1+/− mice which have coronal craniosynostosis.ConclusionOur results suggest that recombinant mouse periostin can inhibit coronal suture cell proliferation and migration and suppress osteogenic differentiation of suture-derived cells via Wnt canonical signaling, as well as ameliorate coronal suture fusion in Twist1+/− mice.Electronic supplementary materialThe online version of this article (10.1186/s12967-018-1454-2) contains supplementary material, which is available to authorized users.

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Section: Resultsmentioning

confidence: 99%

Recombinant mouse periostin ameliorates coronal sutures fusion in Twist1+/− mice

Bai

et al. 2018

J Transl Med

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“…This is noteworthy due to the 3x higher incidence of this phenotype in male patients compared to female patients in our study ( Table 1 ). Dysregulation of androgen hormones has previously been implicated in both syndromic and non-syndromic cases of craniosynostosis [ 52 ] and the androgen receptor is abundantly expressed within the dura matter and calvarial bones of fetal mice [ 53 ]. Increased androgen hormones can also affect expression of TGF-beta, leading to increased osteoblast differentiation and premature suture fusion [ 54 ].…”

Section: Discussionmentioning

confidence: 99%

“…Increased androgen hormones can also affect expression of TGF-beta, leading to increased osteoblast differentiation and premature suture fusion [ 54 ]. Multiple studies of suture closure in rabbits have indicated that treatment with the androgen-blocker flutamide can delay suture fusion and cause increased sutural separation [ 52 , 54 ]. In vitro treatment of fetal murine dural and osteoblast cells with androgen hormone 5-alpha dihydrotestosterone, has also been demonstrated to increase differentiation and proliferation, supporting androgen involvement in suture fusion [ 55 ].…”

Section: Discussionmentioning

confidence: 99%

Transcriptomic Signatures of Single-Suture Craniosynostosis Phenotypes

Lapehn

Gustafson

Timms

et al. 2023

IJMS

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Craniosynostosis is a birth defect where calvarial sutures close prematurely, as part of a genetic syndrome or independently, with unknown cause. This study aimed to identify differences in gene expression in primary calvarial cell lines derived from patients with four phenotypes of single-suture craniosynostosis, compared to controls. Calvarial bone samples (N = 388 cases/85 controls) were collected from clinical sites during reconstructive skull surgery. Primary cell lines were then derived from the tissue and used for RNA sequencing. Linear models were fit to estimate covariate adjusted associations between gene expression and four phenotypes of single-suture craniosynostosis (lambdoid, metopic, sagittal, and coronal), compared to controls. Sex-stratified analysis was also performed for each phenotype. Differentially expressed genes (DEGs) included 72 genes associated with coronal, 90 genes associated with sagittal, 103 genes associated with metopic, and 33 genes associated with lambdoid craniosynostosis. The sex-stratified analysis revealed more DEGs in males (98) than females (4). There were 16 DEGs that were homeobox (HOX) genes. Three TFs (SUZ12, EZH2, AR) significantly regulated expression of DEGs in one or more phenotypes. Pathway analysis identified four KEGG pathways associated with at least one phenotype of craniosynostosis. Together, this work suggests unique molecular mechanisms related to craniosynostosis phenotype and fetal sex.

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“…As most cases of craniosynostosis are non-syndromic with no identified genetic mutation efforts are now focusing on the association of potential mediators on calvarial growth and development and synostosis [ 51 , 52 ]. SSRI use (exposure to fetus through blood/placental barrier) has been identified as having an elevated risk association for craniosynostosis [ 1 , 2 , 4 , 5 , 18 , 19 ].…”

Section: Discussionmentioning

confidence: 99%

Effects of Citalopram on Sutural and Calvarial Cell Processes

et al. 2015

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The use of selective serotonin reuptake inhibitors (SSRIs) for the treatment of depression during pregnancy is suggested to increase the incidence of craniofacial abnormalities including craniosynostosis. Little is known about this mechanism, however based on previous data we propose a mechanism that affects cell cycle. Excessive proliferation, and reduction in apoptosis may lead to hyperplasia within the suture that may allow for differentiation, bony infiltration, and fusion. Here we utilized in vivo and in vitro analysis to investigate this proposed phenomenon. For in vivo analysis we used C57BL–6 wild-type breeders treated with a clinical dose of citalopram during the third trimester of pregnancy to produce litters exposed to the SSRI citalopram in utero. At post-natal day 15 sutures were harvested from resulting pups and subjected to histomorphometric analysis for proliferation (PCNA) and apoptosis (TUNEL). For in vitro studies, we used mouse calvarial pre-osteoblast cells (MC3T3-E1) to assess proliferation (MTS), apoptosis (Caspase 3/7-activity), and gene expression after exposure to titrated doses of citalopram. In vivo analysis for PCNA suggested segregation of effect by location, with the sagittal suture, showing a statistically significant increase in proliferative response. The coronal suture was not similarly affected, however there was a decrease in apoptotic activity at the dural edge as compared to the periosteal edge. No differences in apoptosis by suture or area due to SSRI exposure were observed. In vitro results suggest citalopram exposure increased proliferation and proliferative gene expression, and decreased apoptosis of the MC3T3-E1 cells. Decreased apoptosis was not confirmed in vivo however, an increase in proliferation without a concomitant increase in apoptosis is still defined as hyperplasia. Thus prenatal SSRI exposure may exert a negative effect on post-natal growth through a hyperplasia effect at the cranial growth sites perhaps leading to clinically significant craniofacial abnormalities.

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The effects of testosterone on craniosynostotic calvarial cells: a test of the gene/environmental model of craniofacial anomalies

Cited by 6 publications

References 37 publications

Recombinant mouse periostin ameliorates coronal sutures fusion in Twist1+/− mice

Recombinant mouse periostin ameliorates coronal sutures fusion in Twist1+/− mice

Transcriptomic Signatures of Single-Suture Craniosynostosis Phenotypes

Effects of Citalopram on Sutural and Calvarial Cell Processes

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