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FURTHER DEFINING THE ROLE OF RANK/RANKL/OPG AXIS IN CRANIAL SUTURE BIOLOGY.
Presenter: Maureen Beederman, Medical Student
Co-Authors: Lee JC; Rajan M; Kim S; He TC; Reid RR
University of Chicago

Background: Craniosynostosis, or the premature fusion of cranial sutures, is a condition that affects approximately 1 in 2,500 live births worldwide. Much research on this topic has shown that osteoblasts are implicated in the complex mechanisms that lead to early suture fusion. However, relatively little is known about the role of osteoclasts in this process. Past work from our lab suggests that the RANK-RANKL-OPG pathway involved in osteoclastogenesis is dysregulated in patients with craniosynostosis. Our work further examines the role of OPG, a soluble inhibitor of the RANK system, in this process using knockout technology.

Methods: Animal and human studies were approved by the University of Chicago Animal Care and Use Committee (IACUC) and the University of Chicago Institutional Review Board (IRB). Patient samples were collected during cranial vault reconstruction surgery and analyzed for RANK and OPG protein expression using immunohistochemistry and Western blotting techniques. Wild-type, OPG +/-, and OPG-/- mice were bred and imaged by micro-CT scans at 2, 5, 7, 9, and 12 weeks. Craniometric analysis and suture density measurements were performed using Amgen image analysis software.

Results: Results from Western blotting show that OPG protein expression is increased in the human craniosynostotic samples compared to patent control samples. In murine calvarial specimens, RANK knockdown using adenovirus-expressed si RNA targeting RANK yields higher intrasutural bone density compared to control (ad-GFP) groups. Preliminary data from OPG knockout mice suggest that an upregulation of osteoclast activity leads to alterations in cranial and suture morphology. MicroCT analysis of the posterofrontal suture indicates a decrease in bone density in these mice. Craniometric analysis also elucidates the effects of OPG deficiency on cranial development and morphology.

Conclusions: OPG, the soluble inhibitor of the RANK-RANKL signaling pathway, appears to aid in regulation of suture patency and cranial morphology in the mouse. Further studies focusing on osteoclast biology in diseased and patent sutures are warranted.


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