Noma: A Neglected Area for Research.

Noma, a debilitating and destructive orofacial gangrene, remains endemic in the poor countries of sub-Saharan Africa and other noma hotbeds across the globe, mainly in countries characterized as underdeveloped economies with significant impoverished populations. Noma mostly affects children and infants. This is in spite of the universally held notion that noma is a preventable disease. Indeed, the current noma status quo has been cast as a human rights shortfall, since this devasting disease overwhelmingly affects children from poor countries. At the recently held Noma Research Day, a renewed call for the World Health Organization (WHO) to recognize and include noma as one of the neglected tropical diseases was accompanied by a recognition that research into all aspects of noma has waned or remained completely lacking-particularly that which addresses the basic science questions of the etiology, pathophysiology/pathobiology, and underlying mechanisms of the disease. Yet, a lack of incremental knowledge on the various aspects of noma continues to hamper our composite understanding of its biology. Without a fundamental understanding of the biology of noma, current preventive measures and treatment modalities will continue to fall short of the goals of prevention and eradication. This opinion piece draws renewed attention to the urgency of listing noma as a neglected tropical disease by the WHO. It also calls for major international research funding agencies, including the WHO and the National Institutes of Health, to renew their resolve to robustly fund structured, collaborative, and coordinated proposals that address questions on the epidemiology, etiology, pathophysiology/pathobiology, and molecular mechanisms of the disease. This is with a view to achieving more effective public health approaches toward prevention and to designing potential therapeutic regimens for early lesions. These steps are key to the ultimate eradication of noma.

Matrix metalloproteinase 20-dentin sialophosphoprotein interaction in oral cancer.

Matrix metalloproteinase 20 (MMP-20), widely regarded as tooth specific, participates with MMP-2 in processing dentin sialophosphoprotein (DSPP) into dentin sialoprotein, dentin phosphoprotein, and dentin glycoprotein. In biochemical system, MMP-2, MMP-3, and MMP-9 bind with high affinity to, and are activated by, specific small integrin-binding ligand N-linked glycoproteins (SIBLINGs): bone sialoprotein, osteopontin, and dentin matrix protein 1, respectively. Subsequent reports documented possible biological relevance of SIBLING-MMP interaction in vivo by showing that SIBLINGs are always coexpressed with their MMP partners. However, the cognate MMPs for 2 other SIBLINGs-DSPP and matrix extracellular phosphogylcoprotein-are yet to be identified. Our goal was to investigate MMP-20 expression and to explore preliminary evidence of its interaction with DSPP in oral squamous cell carcinomas (OSCCs). Immunohistochemistry analysis of sections from 21 cases of archived human OSCC tissues showed immunoreactivity for MMP-20 in 18 (86%) and coexpression with DSPP in all 15 cases (71%) positive for DSPP. Similarly, 28 (93%) of 30 cases of oral epithelial dysplasia were positive for MMP-20. Western blot and quantitative real-time polymerase chain reaction analysis on OSCC cell lines showed upregulation of MMP-20 protein and mRNA, respectively, while immunofluorescence showed coexpression of MMP-20 and DSPP. Colocalization and potential interaction of MMP-20 with dentin sialoprotein was confirmed by coimmunoprecipitation and mass spectrometry analysis of immunoprecipitation product from OSCC cell lysate, and in situ proximity ligation assays. Significantly, results of chromatin immunoprecipation revealed a 9-fold enrichment of DSPP at MMP-20 promoter-proximal elements. Our data provide evidence that MMP-20 has a wider tissue distribution than previously acknowledged. MMP-20-DSPP specific interaction, excluding other MMP-20-SIBLING pairings, identifies MMP-20 as DSPP cognate MMP. Furthermore, the strong DSPP enrichment at the MMP-20 promoter suggests a regulatory role in MMP-20 transcription. These novel findings provide the foundation to explore the mechanisms and significance of DSPP-MMP-20 interaction in oral carcinogenesis.

Expression of SIBLINGs and their partner MMPs in salivary glands.

Three members of the SIBLING family of integrin-binding phosphoglycoproteins (bone sialoprotein, BSP; osteopontin, OPN; and dentin matrix protein-1, DMP1) were recently shown to bind with high affinity (nM) and to activate 3 different matrix metalloproteinases (MMP-2, MMP-3, and MMP-9, respectively) in vitro. The current study was designed to document the possible biological relevance of the SIBLING-MMP activation pathway in vivo by showing that these 3 SIBLINGs and their known MMP partners are co-expressed in normal adult tissue. BSP, OPN, and DMP1 were invariably co-expressed with their partner MMPs in salivary glands of humans and mice. The 2 SIBLING proteins without known MMP partners, dentin sialophosphoprotein (DSPP) and matrix extracellular phosphoglycoprotein (MEPE), were also expressed in salivary glands. Expression of all SIBLINGs in this normal, non-mineralizing epithelial tissue suggests that they serve at least one function in vivo other than directly promoting matrix mineralization--a function we hypothesize involves local activation of MMPs.

Distribution of immunoreactive transforming growth factor-alpha in non-neoplastic human salivary glands.

The distribution of immunoreactive transforming growth factor-alpha (TGF-alpha) was studied in non-neoplastic human major and minor salivary glands using an immunoperoxidase assay in conjunction with an antiserum to human TGF-alpha. The ductal cell components of all major and minor salivary glands were found to contain significant amounts of TGF-alpha immunoreactivity. In contrast, acinar and myoepithelial cells consistently lacked immune reaction product in both types of glands. Occasionally, an asynchronous pattern of TGF-alpha ductal cell immunoreactivity was observed in specific ducts within a section. Also, intraductal secretions, when present, were found to contain TGF-alpha immunoreactive material. Ductal cells and connective tissue from salivary glands samples showing significant lymphocytic infiltration and loss of acinar cells exhibited higher levels of TGF-alpha immunoreactivity than normal salivary gland samples. These observations demonstrate, for the first time, the presence of TGF-alpha immunoreactivity in specific structural components of non-neoplastic human major and minor salivary glands. It will be important in future studies to determine whether alterations in TGF-alpha expression are detectable in diverse types of salivary gland tumors.