Estrogen/estrogen receptor alpha signaling in mouse posterofrontal cranial suture fusion.
BACKGROUND
While premature suture fusion, or craniosynostosis, is a relatively common condition, the cause is often unknown. Estrogens are associated with growth plate fusion of endochondral bones. In the following study, we explore the previously unknown significance of estrogen/estrogen receptor signaling in cranial suture biology.


RESULTS
Firstly, estrogen receptor (ER) expression was examined in physiologically fusing (posterofrontal) and patent (sagittal) mouse cranial sutures by quantitative RT-PCR. Next, the cranial suture phenotype of ER alpha and ER beta knockout (alphaERKO, betaERKO) mice was studied. Subsequently, mouse suture-derived mesenchymal cells (SMCs) were isolated; the effects of 17-beta estradiol or the estrogen antagonist Fulvestrant on gene expression, osteogenic and chondrogenic differentiation were examined in vitro. Finally, in vivo experiments were performed in which Fulvestrant was administered subcutaneously to the mouse calvaria. Results showed that increased ERalpha but not ERbeta transcript abundance temporally coincided with posterofrontal suture fusion. The alphaERKO but not betaERKO mouse exhibited delayed posterofrontal suture fusion. In vitro, addition of 17-beta estradiol enhanced both osteogenic and chondrogenic differentiation in suture-derived mesenchymal cells, effects reversible by Fulvestrant. Finally, in vivo application of Fulvestrant significantly diminished calvarial osteogenesis, inhibiting suture fusion.


CONCLUSIONS
Estrogen signaling through ERalpha but not ERbeta is associated with and necessary for normal mouse posterofrontal suture fusion. In vitro studies suggest that estrogens may play a role in osteoblast and/or chondrocyte differentiation within the cranial suture complex.
James
Aaron W
AW
Hagey Pediatric Regenerative Research Laboratory, Department of Surgery, Division of Plastic and Reconstructive Surgery, Stanford University School of Medicine, Stanford, California, USA.
Theologis
Alexander A
AA
Brugmann
Samantha A
SA
Xu
Yue
Y
Carre
Antoine L
AL
Leucht
Philipp
P
Hamilton
Katherine
K
Korach
Kenneth S
KS
Longaker
Michael T
MT
D000818:Animals; D002454:Cell Differentiation; D049109:Cell Proliferation; D003393:Cranial Sutures / Q000378:metabolism* / Q000473:pathology; D004958:Estradiol / Q000031:analogs & derivatives / Q000378:metabolism / Q000494:pharmacology; D004965:Estrogen Antagonists; D047628:Estrogen Receptor alpha / Q000378:metabolism*; D004967:Estrogens / Q000378:metabolism*; D000077267:Fulvestrant; D005786:Gene Expression Regulation; D008648:Mesoderm / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction
D004965:Estrogen Antagonists; D047628:Estrogen Receptor alpha; D004967:Estrogens; D000077267:Fulvestrant; D004958:Estradiol