title: The effects of testosterone on craniosynostotic calvarial cells: a test of the gene/environmental model of craniofacial anomalies.
abstract: BACKGROUND
  The gene-environmental interaction model for craniofacial development proposes that if a genetic predisposition for an anomaly is coupled with an environmental factor that can exacerbate this predisposition, more severe phenotypes will result. Here, we utilize cells derived from our non-syndromic rabbit model of craniosynostosis to test the hypothesis that an insult, testosterone (TP) administration (exogenous source) will alter the osteogenic activity of these cells.
  
  
  METHODS
  Calvarial cells from wild-type (WT) (N=13) or craniosynostotic (CS) rabbits (N=11) were stimulated with TP, an androgen receptor blocker, flutamide, and combined treatments. Proliferation and differentiation assays were conducted after 7 days. anova and t-tests were used to determine differences in stimulation and cell type.
  
  
  RESULTS
  The CS cells had significantly greater proliferation after TP administration compared to WT. There were no appreciable changes in differentiation after TP stimulation. Flutamide administration or combined TP and flutamide administration decreased both proliferation and differentiation for both cell types similarly.
  
  
  CONCLUSIONS
  Testosterone exposure caused an increase in cell proliferation for CS osteoblast cells. However, a therapy targeted to mitigate this response (flutamide therapy) similarly affected CS and WT cells, suggesting that the administration of flutamide or TP in the presence of flutamide decreases osteogenesis of these cells. Thus, although our data support a mechanism of gene-environmental interaction, these results would not support a therapeutic intervention based on this interaction.
authors.affiliation: Pediatric Craniofacial Biology Laboratory, Division of Plastic and Reconstructive Surgery, Department of Surgery, Children's Hospital of Pittsburgh, University of Pittsburgh, Pittsburgh, PA, USA.
authors.forename: J J
authors.initials: JJ
authors.lastname: Cray
authors.forename: E L
authors.initials: EL
authors.lastname: Durham
authors.forename: M A
authors.initials: MA
authors.lastname: Smalley
authors.forename: D N
authors.initials: DN
authors.lastname: Finegold
authors.forename: M I
authors.initials: MI
authors.lastname: Siegel
authors.forename: J E
authors.initials: JE
authors.lastname: Losee
authors.forename: M P
authors.initials: MP
authors.lastname: Mooney
authors.forename: G M
authors.initials: GM
authors.lastname: Cooper
mesh_terms: D000469:Alkaline Phosphatase / Q000032:analysis; D000726:Androgen Antagonists / Q000008:administration & dosage / Q000494:pharmacology; D000728:Androgens / Q000008:administration & dosage / Q000494:pharmacology*; D000818:Animals; D015415:Biomarkers / Q000032:analysis; D018929:Cell Culture Techniques; D002454:Cell Differentiation / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D003398:Craniosynostoses / Q000235:genetics / Q000473:pathology* / Q000503:physiopathology; D004195:Disease Models, Animal; D004338:Drug Combinations; D005485:Flutamide / Q000008:administration & dosage / Q000494:pharmacology; D059647:Gene-Environment Interaction; D010006:Osteoblasts / Q000187:drug effects* / Q000473:pathology; D010012:Osteogenesis / Q000187:drug effects; D011817:Rabbits; D012886:Skull / Q000187:drug effects* / Q000473:pathology; D013739:Testosterone / Q000008:administration & dosage / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D013997:Time Factors
chemical_list: D000726:Androgen Antagonists; D000728:Androgens; D015415:Biomarkers; D004338:Drug Combinations; D013739:Testosterone; D005485:Flutamide; D000469:Alkaline Phosphatase