Discussion: Whole-Proteome Analysis of Human Craniosynostotic Tissue Suggests a Link between Inflammatory Signaling and Osteoclast Activation in Human Cranial Suture Patency

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The classic theories explaining craniosynostosis, initially promulgated by Virchow in the mid-1800s and then almost a century later by Moss, have given way to a better understanding of some of the complex biological interactions associated with anomalous calvarial sutural fusions.1,2 Gene mutations underlying those syndromic craniosynostoses noted to follow Mendelian inheritance patterns were the first to be elucidated. Until recently, the nonsyndromic single-sutural craniosynostoses were generally thought to result from external or environmental factors. However, the observations that the recurrence risk for isolated craniosynostosis was slightly elevated in affected families and that the incidence for this condition was greater in monozygotic versus dizygotic twins, both suggested unrecognized genetic influences.3,4 As testing panels have become more sophisticated, over 50 different mutations have now been associated with nonsyndromic craniosynostoses, substantiating an argument favoring more routine exome/whole genome sequencing.5 Knowledge of specific gene mutations can help us to better understand downstream effects on cranial sutures; concurrent with this progressive appreciation for heretofore unrecognized genetic influences has come a deeper exploration into the biomolecular mechanisms underlying these anomalous fusions. Regional effects of the dura on cranial sutures have been demonstrated in the murine model, a finding underscoring the role of dural reflections as critically important chemical highways, which serve to facilitate the transport of factors regulating suture-dependent growth.6,7 Fibroblastic growth factors, transforming growth factor-β, bone morphogenic protein antagonists (noggin), Hedgehog signaling, and even androgens have all been implicated in anomalous sutural fusions.8,9
In this current issue of Plastic and Reconstructive Surgery, Lyon et al. investigate the role played by osteoclasts in children with craniosynostosis by focusing on proteins known to be either osteoclastic regulators or proinflammatory. By using protein extraction techniques, they examined expression differences between fused and patent sutures in five children. Four had midline fusions (three sagittal and one metopic) and one had a lateral fusion (unilateral coronal), with ages at sampling ranging from 3 to 15 months. Three proteins—collagen 6A, fibromodulin, and adipocyte enhancer-binding protein 1—were found to be highly expressed in patent sutures, suggesting that the maintenance of an inflammatory state might be important for sutural patency. Moreover, osteomodulin, thought to be an osteoclastic-induced osteoblast maturation marker, was found to be differentially up-regulated in fused sutures. These findings led the authors to speculate that osteoclastic dysregulation might play an important role in abnormal sutural fusions. They are also appropriately restrained in not trying to draw any substantive conclusions, recognizing that their data were derived from a sampling of disparate sutures in just five patients. Probably the most important caveat to this interesting study is that their samples were taken in sutures that were already closed, in what was likely a more homeostatic state, and not during active sutural closure, a process that most probably occurred in utero. In spite of this temporal sampling challenge, disruptions in the normal balance between osteoclastic and osteoblastic activity would seem to be most likely playing some important role in the development of anomalous sutural fusions. This current study has provided us with further insights into these complex interactions. As our understanding of those genetic and biological processes underlying craniosynostosis improves, there remains the tantalizing potential that novel treatment strategies might someday come to light.
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