Surgical correction of unilateral coronal synostosis offers a unique opportunity to examine the molecular differences between an abnormal and a normal cranial suture. We isolated and identified a cDNA fragment whose expression was up-regulated in the premature fusing and fused coronal sutures, as compared with normal coronal sutures. The nucleotide sequence of the full-length cDNA of this gene, human NELL-1, has ∼61% homology with the chicken Nel gene. Both chicken Nel and human NELL-1 are comprised of six epidermal growth factor-like repeats. The human NELL-1 messages were localized primarily in the mesenchymal cells and osteoblasts at the osteogenic front, along the parasutural bone margins, and within the condensing mesenchymal cells of newly formed bone in sites of premature sutural fusion. Human multiorgan tissue mRNA blot showed that NELL-1 was specifically expressed in fetal brain but not in fetal kidney, liver, or lung. We also showed that Nell-1 was expressed in rat calvarial osteoprogenitor cells and was largely absent in rat tibiae and fibroblast cell cultures. In conclusion, our data suggest that the NELL-1 gene is preferentially expressed in cranial intramembranous bone and neural tissue (both of neural crest cell origin) and is up-regulated during unilateral premature closure of the coronal suture. The precise role of this gene is unknown. (J Bone Miner Res 1999;14:80-89)

No abstract

Keloids are an excessive accumulation of extracellular matrix. Although numerous studies have shown elevated plasminogen activator inhibitor-1 (PAI-1) levels in keloid fibroblasts compared with those of normal skin. Their specific mechanisms involved in the differential expression of PAI-1 in these cell types. In this study, the upregulation of PAI-1 expression is demonstrated in keloid tissues and their derived dermal fibroblasts, attesting to the persistence, if any, of fundamental differences between in vivo and in vitro paradigms. We further examined the mechanisms involved in hypoxia-induced regulation of PAI-1 gene in dermal fibroblast derived from keloid lesions and associated clinically normal peripheral skins from the same patient. Primary cultures were exposed to an environmental hypoxia or desferroxamine. We found that the hypoxia-induced elevation of PAI-1 gene appears to be regulated at both transcriptional and post-transcriptional levels in keloid fibroblasts. Furthermore, our results showed a consistent elevation of HIF-1alpha protein level in keloid tissues compared with their normal peripheral skin controls, implying a potential role as a biomarker for local skin hypoxia. Treatment with antisense oligonucleotides against hypoxia-inducible factor 1alpha (HIF-1alpha) led to the downregulation of steady-state levels of PAI-1 mRNA under both normoxic and hypoxic conditions. Conceivably, our results suggest that HIF-1alpha may be a novel therapeutic target to modulate the scar fibrosis process.

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Excessive scar or keloid shares common features of a benign dermal growth. Yet, in contrast to malignant tumor, a keloid does not expand beyond the dermis. What triggers the continuing growth of a benign lesion? Deficient or overabundant levels of vascular endothelial growth factor have been reported to contribute to impaired or excessive wound healing. Although numerous studies have examined the pathophysiology of impaired wounds, little information has been provided on mechanisms of exuberant healing. The molecular basis of keloid formation is governed by the interplay of cellular signaling pathways, specific target gene activation, and the nature of the microenvironment. Recent works have demonstrated an accumulation of hypoxia-inducible factor-1α protein in freshly biopsied keloid tissues, thus providing first evidence that a local state of hypoxia exists in keloids. Our findings and the findings of others support at least two plausible mechanisms implicated in the development of fibrotic wounds, a state of ongoing fibroplasia or inflammation and an excessive accumulation of extracellular matrix. This article will review recent works examining the potential role of vascular endothelial growth factor in keloid pathogenesis with particular focus on its involvement in the two proposed pathological processes, a prolonged inflammation and an altered balance in extracellular matrix metabolism.