Plastic Surgery Research Council
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PSRC 60th Annual Meeting
Program and Abstracts

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Whole-Proteome Analysis of Craniosynostotic Tissue Suggests a Link Between Inflammatory Signaling and Premature Suture Fusion
Sarah Lyon, BS1, Michael Januszyk, MD2, Anoop Mayampurath, PhD1, Darrel J. Waggoner, MD1, David M. Frim, MD1, Tong-Chuan He, MD, PhD1, Russell R. Reid, MD PhD1.
1University of Chicago, Chicago, IL, USA, 2Stanford University, Stanford, CA, USA.

PURPOSE:
Craniosynostosis is a congenital disorder associated with premature cranial suture fusion, which can be associated with developmental delay, hearing and visual impairment, and craniofacial asymmetries. Despite its marked phenotype and relatively high prevalence, the pathobiology of this disease remains poorly understood. Here we apply proteome-wide analysis using mass spectrometry to explore the biological factors underlying premature suture fusion.
METHODS:
Fused and patent suture samples were obtained from five craniosynostotic patients (ages 3 to 12 months) undergoing cranial vault reconstruction at a single academic medical center in 2013 (IRB #16045B). Protein was extracted from tissue samples and interrogated using mass spectrometry. Differential protein expression between fused and patent cranial sutures was determined using the maximum likelihood-based G-test with q-value cutoffs of 0.5 following correction for multiple hypothesis testing. Hierarchical clustering of expression data for each group was performed, followed by canonical pathway calculations and network analysis.
RESULTS:
Proteins differentially expressed in patent vs. fused sutures included pro-osteogenic genes such as POSTN and OGN, as well as pro-inflammatory mediators including FMOD and multiple collagen proteins. The top canonical pathways linking these proteins were Connective Tissue Disorder, Dermatological Disease, and Organismal Injury. Interestingly, osteomodulin (ODM), a key signaling molecule mediating osteoblast-osteoclast interactions in bone resorption, was significantly up-regulated in prematurely fused sutures. Biological networks were constructed separately using proteins up- and down-regulated in fused sutures and then merged to generate a super-network based on overlapping pathway topology (Figure 1). Central elements of this network include key osteogenic and inflammatory molecules such as TGFB and numerous interleukins.
CONCLUSION:
Taken together, these results suggest a potential link between dysregulation of inflammatory signaling and early suture fusion. Given the wide array of anti-inflammatory agents currently available, these preliminary findings may have considerable therapeutic implications, although additional validation studies will be required.


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