Whole-Proteome Analysis and Immunohistochemical Staining of Craniosynostotic Tissue Suggests a Link between Inflammatory Signaling and Osteoclast Activation in Cranial Suture Patency
Sarah Lyon, BA.
University of Chicago Pritzker School of Medicine, Chicago, IL, USA.
Nonsyndromic craniosynostosis can be associated with developmental delay, hearing and visual impairment, and craniofacial asymmetries. Despite its relatively high prevalence, the pathophysiology remains poorly understood. We previously identified proteins differentially expressed in patent and fused cranial sutures by comparing their respective proteomes. Here we analyze these proteins using immunohistochemistry.
Fused and patent suture samples were obtained from five craniosynostotic patients (ages 3-12 months) undergoing cranial vault reconstruction at a single academic medical center. Protein was extracted from samples and interrogated using mass spectrometry. Differential protein expression was determined using the maximum likelihood-based G-test with q-value cutoffs of 0.5 following correction for multiple hypothesis testing. Immunolocalization of lead protein candidates was performed in patent and fused sutures.
Proteins differentially expressed in patent versus fused sutures included the pro-inflammatory mediator FMOD and multiple collagen proteins including Col6A1. Maximum likelihood-based G-test suggested Col6A1 and FMOD are highly expressed in patent sutures compared to fused. Immunohistochemical staining of sutures demonstrated Col6A1 upregulation in patent sutures (A) compared to fused (B).
These results suggest Col6A1 may aid in the regulation of suture patency. Previous reports linking Col6A1 to the RANK-RANKL osteoclast activation pathway in rheumatoid arthritis suggest a link between osteoclast and inflammatory signaling inactivation and premature cranial suture fusion. These preliminary findings may have considerable therapeutic implications, although additional validation studies are required.
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