title: Force-induced craniosynostosis via paracrine signaling in the murine sagittal suture.
abstract: BACKGROUND
  The role of genetic phenomena has been given central importance in the development of craniosynostosis. Proponents have dismissed the role of force as a key etiologic factor. Nonetheless, compressive forces on the developing calvarium have been shown to result in premature suture fusion. The purpose of this study was to determine whether cyclical loading of the murine calvarium could induce suture fusion in cocultured calvarial specimens.
  
  
  METHODS
  Calvarial coupons from postnatal day 21, B6CBA wild-type mice (n = 24) were harvested and cultured. A custom appliance capable of delivering compressive loads was applied perpendicular to the sagittal suture in vitro. Six coupons were subjected to 0.3 g of force for 30 minutes each day for a total of 14 days. Six additional coupons were cocultured within the same medium. Control groups were devised. Histologic analysis of suture phenotype was performed.
  
  
  RESULTS
  Sagittal sutures cocultured with unloaded specimens remained patent. In contradistinction, 4 of 6 specimens cocultured with loaded coupons demonstrated craniosynostosis (P = 0.03). Increased osteoid, alkaline phosphatase staining, and bone sialoprotein expression were observed when compared with matched controls.
  
  
  CONCLUSIONS
  An in vitro model of force-induced craniosynostosis via paracrine effects has been devised. Premature fusion of the murine sagittal suture was induced in unloaded specimens cocultured with cyclically loaded calvarial coupons. These results implicate that abnormal forces may act through soluble factors to cause premature suture fusion in vitro. The findings support our global hypothesis that epigenetic phenomena play a crucial role in the pathogenesis of nonsyndromic craniosynostosis.
authors.affiliation: Section of Plastic Surgery, Department of Surgery, University of Michigan, Ann Arbor, Michigan, USA.
authors.forename: Adam J
authors.initials: AJ
authors.lastname: Oppenheimer
authors.forename: Samuel T
authors.initials: ST
authors.lastname: Rhee
authors.forename: Steven A
authors.initials: SA
authors.lastname: Goldstein
authors.forename: Steven R
authors.initials: SR
authors.lastname: Buchman
mesh_terms: D000469:Alkaline Phosphatase / Q000378:metabolism; D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D018920:Coculture Techniques; D003393:Cranial Sutures / Q000254:growth & development* / Q000378:metabolism / Q000473:pathology; D003398:Craniosynostoses / Q000235:genetics* / Q000473:pathology*; D004195:Disease Models, Animal; D058574:Integrin-Binding Sialoprotein / Q000378:metabolism; D051379:Mice; D019899:Paracrine Communication / Q000235:genetics*; D010641:Phenotype; D012886:Skull / Q000254:growth & development* / Q000378:metabolism / Q000473:pathology; D013314:Stress, Mechanical
chemical_list: D015415:Biomarkers; D058574:Integrin-Binding Sialoprotein; D000469:Alkaline Phosphatase