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University of British Columbia, Faculty of Dentistry, Department of Oral Biological and Medical Sciences, Laboratory of Periodontal Biology, 2199 Wesbrook Mall, Vancouver, BC, Canada V6T 1Z3;
* corresponding author, lhakkine{at}interchange.ubc.ca
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONCLINICAL PRESENTATIONHISTOLOGICAL CHARACTERISTICSCELLULAR AND MOLECULAR CHANGESGENETIC CHARACTERISTICSSOS-1 GENE MUTATIONPUTATIVE ROLE OF THE...DIRECTIONS FOR FUTURE RESEARCHREFERENCES |
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KEY WORDS: gingiva • overgrowth • hereditary • pathogenesis • SOS-1
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONCLINICAL PRESENTATIONHISTOLOGICAL CHARACTERISTICSCELLULAR AND MOLECULAR CHANGESGENETIC CHARACTERISTICSSOS-1 GENE MUTATIONPUTATIVE ROLE OF THE...DIRECTIONS FOR FUTURE RESEARCHREFERENCES |
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CLINICAL PRESENTATION |
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TOPABSTRACTINTRODUCTIONCLINICAL PRESENTATIONHISTOLOGICAL CHARACTERISTICSCELLULAR AND MOLECULAR CHANGESGENETIC CHARACTERISTICSSOS-1 GENE MUTATIONPUTATIVE ROLE OF THE...DIRECTIONS FOR FUTURE RESEARCHREFERENCES |
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). Localized forms of HGF usually affect the maxillary tuberosities and the labial gingiva around the mandibular molars. However, the symmetric generalized form of HGF that affects the labial, lingual, and palatal gingiva is the most common (Baptista, 2002; Kelekis-Cholakis et al., 2002). Males and females are affected equally. Unlike drug-induced gingival overgrowth, HGF is not influenced by plaque, and the incidence and severity of the disease appear to depend on the penetrance of the mutated gene (Hart et al., 1998; Xiao et al., 2001; Ye et al., 2005). Enlarged gingiva may be normal in color or erythematous, and consists of dense fibrous tissue that feels firm and nodular on palpation. Although the alveolar bone is usually unaffected, gingival excess results in pseudopocketing and periodontal problems, due to difficulties in daily oral hygiene. The overgrowth may also result in functional and esthetic concerns, create diastemas, impede or delay tooth eruption, and create changes in facial appearance as a result of lip protrusion. Severe overgrowth can result in crowding of the tongue, speech impediments, and difficulty with mastication, and can prevent normal closure of lips (Shafer, 1983; Lynch et al., 1994).
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HISTOLOGICAL CHARACTERISTICS |
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TOPABSTRACTINTRODUCTIONCLINICAL PRESENTATIONHISTOLOGICAL CHARACTERISTICSCELLULAR AND MOLECULAR CHANGESGENETIC CHARACTERISTICSSOS-1 GENE MUTATIONPUTATIVE ROLE OF THE...DIRECTIONS FOR FUTURE RESEARCHREFERENCES |
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). Epithelial hyperplasia can also occur as a consequence of acanthosis, but this was found only in areas of chronic inflammation in HGF (Farrer-Brown et al., 1972; Raeste et al., 1978). Characteristic of fibrosis, the connective tissue in HGF exhibits an accumulation of excess collagen, and elastic and oxytalan fibers, but has relatively few fibroblasts and blood vessels (Chavrier and Couble, 1979; Hart et al., 2000; Baptista, 2002; Sakamoto et al., 2002; Doufexi et al., 2005) (Fig. 1). Enlarged fibroblasts appear to alternate with thin and thick collagen fibrils. Unlike in normal gingiva, the collagen fiber bundles are oriented mostly parallel to one another (Kelekis-Cholakis et al., 2002; Casavecchia et al., 2004) (Fig. 1). Although a rare finding, small osseous calcifications and abundant neurovascular bundles may also be present (Gunhan et al., 1995; Kelekis-Cholakis et al., 2002). HGF does not usually involve inflammation, and local accumulation of inflammatory cells can be found only in cases where pseudo-pocketing resulted in plaque accumulation (Shafer, 1983). Diagnosis of HGF is based on medical history and clinical examination, since there are currently no specific immunohistochemical markers available. |
CELLULAR AND MOLECULAR CHANGES |
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TOPABSTRACTINTRODUCTIONCLINICAL PRESENTATIONHISTOLOGICAL CHARACTERISTICSCELLULAR AND MOLECULAR CHANGESGENETIC CHARACTERISTICSSOS-1 GENE MUTATIONPUTATIVE ROLE OF THE...DIRECTIONS FOR FUTURE RESEARCHREFERENCES |
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Phenotypically Different Fibroblast Subpopulations
Some studies suggest that predominance of certain "active" fibroblast subpopulations may explain the susceptibility of certain individuals to gingival overgrowth. Phenotypically and functionally distinct gingival fibroblast subpopulations co-exist within and between individuals (Häkkinen and Larjava, 1992; Hassell, 1993). The correlation between onset of HGF and tooth eruption implies that selection or activation of fibroblasts by inflammatory cells, or as a result of trauma, may initiate gingival overgrowth. Cell culture studies have suggested that fibroblasts from fibrotic tissues remain activated, even in the absence of continuous stimulation (Hassell et al., 1976; Duncan and Berman, 1987; Tipton et al., 2004). Therefore, fibroblasts in HGF could remain active after tooth eruption, possibly due to selective growth of active cell subpopulations that contribute to excess ECM production. This process is similar to wound healing, although, in HGF, this process would be continuously ’turned on’ (Häkkinen et al., 2000).
Cell Proliferation
It is not clear whether increased cell proliferation contributes to HGF. Histologically, HGF shows reduced fibroblast density, and there is no increase in the expression of the proliferation markers PCNA or Ki-67 in fibroblasts as compared with normal tissue (Wright et al., 2001; Martelli-Junior et al., 2005). In contrast, fibroblasts from HGF appear to proliferate faster than normal cells in culture (Tipton et al., 1997; Coletta et al., 1998), although a reduced proliferation rate has also been described (Shirasuna et al., 1988). Recent studies have attempted to uncover some of the molecular mechanisms involved in growth regulation of HGF fibroblasts. The increased proliferation rate of HGF fibroblasts was associated with increased fatty acid synthase (FAS) expression, and the inhibition of FAS reduced proliferation rates to normal levels (Almeida et al., 2005). Elevated c-myc expression was also associated with an increased DNA synthesis rate (Tipton et al., 2004). C-myc is a nuclear proto-oncogene that is expressed by proliferating cells, and its increased expression has been associated with deregulated cell growth (Secombe et al., 2004). Increased proliferation of HGF fibroblasts was also linked to autogenous transforming growth factor-ß (TGF-ß), since neutralizing antibodies to TGF-ß1 reduced proliferation of HGF fibroblasts (de Andrade et al., 2001). However, such an effect for blocking autogenous TGF-ß was not found in another study (Tipton and Dabbous, 1998). The conflicting results regarding fibroblast proliferation in HGF are likely due to genetic heterogeneity of HGF, small sample size, inherent phenotypical heterogeneity of fibroblasts, and different culture conditions.
In contrast to fibroblasts, HGF epithelial cells show an increased frequency of immunostaining of the proliferation markers PCNA or Ki-67, as compared with healthy tissue in vivo (Martelli-Junior et al., 2005). Epidermal growth factor (EGF) and its receptor (EGFR) are important regulators of epithelial cell proliferation (Harris et al., 2003; Jorissen et al., 2003), and they co-localize with PCNA at the tips of rete pegs in HGF (Araujo et al., 2003). Thus, over-expression of EGF or EGFR by the epithelial cells in HGF may have a stimulatory effect on epithelial cell proliferation, resulting in deep rete pegs that extend into the underlying stroma. However, the fact that EGF and EGFR expression was higher in health than in HGF when all epithelial layers were taken into account, and yet their localization was not associated with epithelial cell proliferation, suggests that other mechanisms are also involved (Araujo et al., 2003).
Expression of Transforming Growth Factor-ß and its Receptors
The TGF-ß family of cytokines stimulates fibroblast proliferation and deposition of ECM. TGF-ßs also regulate various functions of epithelial cells, including cell migration, proliferation, and gene expression. There are 3 isoforms of TGF-ß (TGF-ß1, TGF-ß2, and TGF-ß3) that are expressed in humans. The effects of TGF-ß can be exerted in an autocrine or a paracrine fashion by 3 different TGF-ß cell-surface receptors (TGF-ß-RI, TGF-ß-RII, TGF-ß-RIII). The functions of different TGF-ß isoforms are distinct, since TGF-ß1, and possibly TGF-ß2, is involved in the development of fibrosis, while TGF-ß3 appears to prevent it (Verrecchia and Mauviel, 2002; Govinden and Bhoola, 2003; Schiller et al., 2004). Based on immunostaining, all 3 isoforms of TGF-ß can be found in human gingiva, where they are expressed by epithelial cells, inflammatory cells, endothelial cells, and fibroblasts. In HGF, there is a significant proportional increase in fibroblasts expressing TGF-ß1 and TGF-ß3, while the proportion of cells expressing TGF-ß2 is decreased as compared with healthy tissue. In addition, the proportion of TGF-ß-RI/II-positive cells is significantly increased in HGF (Wright et al., 2001). It is not known whether the increase in TGF-ß accounts for biologically active or latent TGF-ß. Most TGF-ß is produced in a latent form that must be activated by mechanisms involving partial proteolysis or conformational changes (Nunes et al., 1998; Sheppard, 2005). Thus, the mechanisms that activate TGF-ß may also play a key role in HGF. Furthermore, ECM contains molecules that inhibit the activity of TGF-ß. For example, the small leucine-rich proteoglycans decorin, biglycan, and fibromodulin, which are also present in human gingiva (Larjava et al., 1992; Häkkinen et al., 1993; Alimohamad et al., 2005; Matheson et al., 2005), can inhibit TGF-ß activity (Hildebrand et al., 1994). Nothing is known about the abundance of these molecules in HGF.
Cell culture experiments have also indicated that HGF fibroblasts produce increased levels of TGF-ß1 and TGF-ß2, which results in increased ECM deposition by an autocrine mechanism specific to HGF fibroblasts (Tipton and Dabbous, 1998; Coletta et al., 1999; Martelli-Junior et al., 2003; Trackman and Kantarci, 2004). In gingival fibroblasts, TGF-ß1 also induces an autocrine expression of connective tissue growth factor (CTGF) (Hong et al., 1999; Leivonen et al., 2005). CTGF may play a role in HGF, since it mediates most of the pro-fibrotic effects of TGF-ß1, and its expression is up-regulated in various fibrotic conditions (Blom et al., 2002).
Extracellular Matrix Production and Degradation
In addition to providing mechanical support, ECM is an important regulator of cell functions. Furthermore, ECM molecules serve as storage for various growth factors and participate in the regulation of their activation (Häkkinen et al., 2000; Li et al., 2003; Midwood et al., 2004). Thus, altered abundance or composition of ECM may play an active part in the pathogenesis of HGF. The hallmark of HGF is the accumulation of excess ECM. Accordingly, production of type I collagen—along with heat-shock protein 47 (Hsp47, a molecular chaperone involved in collagen secretion), glycosaminoglycan, and fibronectin—is increased in cultured HGF fibroblasts (Shirasuna et al., 1988; Tipton et al., 1997; Coletta et al., 1999; Martelli-Junior et al., 2003). The role of TGF-ß in this process is of interest, because expression of TGF-ß is up-regulated in HGF.
TGF-ß can promote ECM accumulation by increasing ECM synthesis. It can also inhibit ECM breakdown by down-regulating matrix metalloproteinase (MMP) expression, and by increasing expression of tissue inhibitors of matrix metalloproteinases (TIMP). TIMPs inhibit MMP activity, and a high ratio of TIMPs to MMPs results in excess collagen accumulation (Steffensen et al., 2001). Exogenous or autocrine TGF-ß1 up-regulates type I collagen and down-regulates MMP-1 (the major collagenase in fibroblasts) expression in gingival fibroblasts (Ravanti et al., 1999a; Leivonen et al., 2002; Ala-aho and Kähäri, 2005). However, expression of TIMP-1 and TIMP-2 has been reported to be down-regulated or unaltered in HGF fibroblasts (Coletta et al., 1999; Martelli-Junior et al., 2003). Thus, it is possible that fibroblasts in HGF, inherently or as a response to elevated TGF-ß activity, produce less MMPs and more ECM proteins as compared with normal cells, resulting in ECM accumulation. Interestingly, HGF may also involve altered cross-linking of collagen, resulting in increased resistance to degradation (Pallos et al., 1997).
MMP-mediated collagen degradation is an important mechanism for ECM turnover in wound healing and inflammation (Steffensen et al., 2001). However, collagen phagocytosis by fibroblasts is one of the major mechanisms of collagen turnover during tissue maintenance. Fibrotic lesions, especially in the absence of inflammation, may arise from a reduction in the proportion of fibroblasts that degrade collagen intracellularly. For example, nifedipine-treated fibroblasts show a dose-dependent decrease in the percentage of phagocytic cells, suggesting that aberrant collagen phagocytosis plays a role in drug-induced gingival overgrowth (McCulloch and Knowles, 1993; McCulloch, 2004). Interestingly, the ECM molecule decorin potently blocks collagen phagocytosis by gingival fibroblasts (Bhide et al., 2005). Thus, changes in the composition of ECM may affect the phagocytic ability of the cells in HGF. Collagen internalization and lysosomal degradation are also mediated by an endocytotic process that involves the cell-surface receptor Endo180 (also called CD280 or urokinase plasminogen activator receptor-associated protein, uPARAP) (East and Isacke, 2002; Behrendt, 2004). Endo180 is expressed by various human gingival cells, including fibroblasts (Honardoust et al., 2006), but its expression and function in HGF have not been studied in detail.
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GENETIC CHARACTERISTICS |
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TOPABSTRACTINTRODUCTIONCLINICAL PRESENTATIONHISTOLOGICAL CHARACTERISTICSCELLULAR AND MOLECULAR CHANGESGENETIC CHARACTERISTICSSOS-1 GENE MUTATIONPUTATIVE ROLE OF THE...DIRECTIONS FOR FUTURE RESEARCHREFERENCES |
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). Several studies have pointed out mutations in chromosome 2 as a possible cause of HGF. Originally, the region of 2p13-p21 in chromosome 2 was associated with a syndromic form of HGF (Fryns, 1996). The affected locus was later refined to encompass the region 2p13-2p16 (Shashi et al., 1999). This region was different from the HGF1 locus 2p21-p22 found in a Brazilian family with an autosomal-dominant, non-syndromic HGF (Hart et al., 1998). In the Brazilian family, the HGF1 locus was confined to a candidate interval, and sequencing of the 16 genes found in this region revealed a mutation in a gene that codes for a guanine nucleotide-exchange factor, son-of-sevenless-1 (SOS-1) (Hart et al., 2002). To determine the generality of the HGF1 locus, these investigators examined another Brazilian family with autosomal-dominant HGF. Interestingly, the findings suggested the presence of another mutation in this region (Hart et al., 2000). Data from four Chinese families mapped a dominant HGF locus also to the region 2p21-2p22 in chromosome 2 (Xiao et al., 2000). In contrast to the Brazilian family, where recombination suppression was found (Hart et al., 1998), similar characteristics were not found in the Chinese families. Furthermore, the SOS-1 locus was likely not affected in the Chinese families, suggesting a different genetic background (Xiao et al., 2000; Hart et al., 2002). Recently, non-syndromic, autosomal-dominant HGF was also linked to yet another region in chromosome 2 (HGF3 or GINGF3, 2p22.3-p23.3). This region contains more than 70 known genes, but specific mutations have not been reported (Ye et al., 2005). In addition, analysis of another Chinese family with autosomal-dominant HGF revealed still another novel locus, HGF2 (GINGF2), in chromosome 5 (5q13-q22), but the specific gene mutation in this region has not been defined (Xiao et al., 2001). Additional chromosomes and gene mutations are associated with syndromic forms of HGF (Table). Thus, HGF is genetically heterogenous and may involve several genes. Remarkably, different forms of HGF display relatively similar histological outcomes, suggesting that the mutations affect different levels of the same cellular or molecular pathways. Discovery of the mutation in SOS-1 will allow investigators, for the first time, to uncover some of the signaling mechanisms involved in HGF.
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SOS-1 GENE MUTATION |
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TOPABSTRACTINTRODUCTIONCLINICAL PRESENTATIONHISTOLOGICAL CHARACTERISTICSCELLULAR AND MOLECULAR CHANGESGENETIC CHARACTERISTICSSOS-1 GENE MUTATIONPUTATIVE ROLE OF THE...DIRECTIONS FOR FUTURE RESEARCHREFERENCES |
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). SOS-1 is essential for normal development, since SOS-1 knock-out mice embryos die at mid-gestation (Wang et al., 1997; Qian et al., 2000). Biochemical analyses and cell culture experiments have shown that, upon growth factor stimulation, SOS-1 activates Ras indirectly by facilitating the exchange of GTP for GDP on Ras (Shapiro, 2002). When bound to GDP, Ras is inactive, while binding to GTP leads to its activation and phosphorylation of ERK1/2 of the mitogen-activated protein kinase (MAPK) signaling pathway. This pathway is one of the key mechanisms for the regulation of cell proliferation, survival, gene expression, and differentiation. The effect of the Ras-ERK1/2 pathway is cell-type-specific and also depends on the duration and intensity of the activation (Agell et al., 2002). Ras can also activate downstream molecules involved in other signaling pathways, including phosphoinositide-3 kinases (PI3Ks), phosphoinositide-specific phospholipase C
(PLC), and the Ral nucleotide exchange factor (RalGDS) family. These pathways have multiple functions in the regulation of cell proliferation, cytoskeletal re-organization, and gene transcription (Cullen and Lockyer, 2002).
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). Activation of Rac regulates the actin remodeling and cytoskeletal organization that is critical for the transport of signaling molecules inside the cell, cell adhesion, and migration. Whether SOS-1 will function as a Ras or Rac exchange factor is dictated by its C-terminal proline-rich region, which contains binding sites for SH3 domains present in both adaptor proteins Grb2 and E3b1 (Nimnual et al., 1998; Scita et al., 1999; Nimnual and Bar-Sagi, 2002; Sondermann et al., 2004). It appears that Grb2 and E3b1 share the same binding site on the SOS-1 molecule. Therefore, competition between these two adaptor proteins for binding to SOS-1 may determine whether the Ras or the Rac pathway gets activated (Li et al., 1993; Cussac et al., 1994; Scita et al., 1999; Innocenti et al., 2002). Phosphorylation of SOS-1 on tyrosine residues by the MAPK pathway does not affect the stability of the SOS-1/E3b1/Eps8 complex, but it disrupts the SOS-1/Grb2 complex (Corbalan-Garcia et al., 1996; Sini et al., 2004). Hence, phosphorylation of SOS-1 provides a mechanism to balance signaling between the Ras and Rac pathways (Sini et al., 2004). In addition to growth factor receptors, certain integrin-type ECM receptors also regulate the Ras and Rac pathways through SOS-1 (Wary et al., 1996, 1998; Mettouchi et al., 2001). Thus, SOS-1 plays a key role in both ECM and growth factor signaling.
Individuals with HGF1 have a single-cytosine insertion in exon 21 of the SOS-1 gene, leading to a frame-shift mutation and an early termination of the protein (Fig. 2B). This mutation results in ~ 20% of the SOS-1 gene being deleted and includes the proline-rich Grb2 and E3b1-binding domain and the 5 MAPK phosphorylation sites (Hart et al., 2002). Interestingly, a similarly engineered shortened SOS-1 protein has enhanced activity as compared with the wild-type molecule in vitro, and in cells engineered to express the mutated protein, the MAPK pathway is continuously active (Wang et al., 1995). This suggests that, in HGF1, mutated SOS-1 is constantly in an activated state, which may increase the activity of the MAPK pathway. A transgenic mouse with constitutively active SOS-1 was also developed. In these mice, the active SOS-1 was expressed in the epithelium under the control of the cytokeratin-5 promoter and resulted in the development of skin tumors, multiple papillomas, and hyperplastic skin (Sibilia et al., 2000). Interestingly, these mice also developed thickening of the tongue epithelium, but it is not known whether they also displayed gingival overgrowth.
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PUTATIVE ROLE OF THE RAS-MAPK PATHWAY IN GINGIVAL OVERGROWTH |
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TOPABSTRACTINTRODUCTIONCLINICAL PRESENTATIONHISTOLOGICAL CHARACTERISTICSCELLULAR AND MOLECULAR CHANGESGENETIC CHARACTERISTICSSOS-1 GENE MUTATIONPUTATIVE ROLE OF THE...DIRECTIONS FOR FUTURE RESEARCHREFERENCES |
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). Interestingly, the Sos-1-Ras-ERK1/2 pathway appears to be a central modulator of expression of the key molecules that are involved in fibrosis and HGF (Fig. 3). For example, activation of this pathway up-regulates the expression of type I collagen, CTGF, TGF-ß, and TIMPs, while it down-regulates the expression of MMPs (Benbow and Brinckerhoff, 1997; Ravanti et al., 1999a,b; Mulder, 2000; Chen et al., 2002; Hall et al., 2003; Leask et al., 2003; Ohnishi et al., 2004; Leivonen et al., 2005; Mulsow et al., 2005). The up-regulation of TGF-ß expression by this pathway is of interest, since TGF-ß is up-regulated in HGF, and it activates the Ras-ERK1/2 pathway. In addition, the induction of the pro-fibrotic molecules by the Ras-ERK1/2 pathway occurs in collaboration with the Smad pathway induced by TGF-ß. For example, co-expression of Smad3 with constitutively active MAPK/ERK kinase (MEK1) induces the expression of CTGF in gingival fibroblasts (Leivonen et al., 2005). Thus, increased activation of the ERK1/2 pathway by constitutively active SOS-1 could drive the fibrosis in HGF. Expression of the key pro-fibrotic molecules is also regulated in collaboration with the Ras-ERK1/2 and Smad pathways at the transcriptional level, where both pathways activate the transcription-factor-activating protein-1 (AP-1) (Yates and Rayner, 2002; Hall et al., 2003) (Fig. 3).
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). Hundreds of Ca2+-binding proteins have been identified, including protein kinases (e.g., calmodulin-dependent protein kinases or CaMKs) and protein phosphatases (e.g., calcineurin). In addition, Ca2+ binds to proteins (e.g., calmodulin) that do not have intrinsic kinase or phosphatase activity, but which, upon binding with Ca2+, regulate functions of calmodulin-binding proteins, Ca2+-dependent enzymes, and ion channels. Ca2+ ions or their interactions with the binding proteins subsequently regulate multiple cell functions, including gene transcription, cell proliferation, development, motility, and secretion (Stull, 2001; Agell et al., 2002; Kahl and Means, 2003). Phenytoin, nifedipine, and cyclosporine A, medications that cause gingival overgrowth, perturb intracellular Ca2+-signaling pathways, suggesting that abnormal Ca2+ signaling is involved in gingival overgrowth (Marshall and Bartold, 1999). Interestingly, the region at 5q13-q22 associated with HGF2 encompasses the calcium/calmodulin-dependent protein kinase IV (CaMKIV) gene that is expressed in gingiva (Xiao et al., 2001). In addition, genes for sodium/calcium exchanger (NCX1) and calmodulin-2 reside within the chromosome 2p21 interval that co-segregates with HGF (Shieh et al., 1992; Berchtold et al., 1993; Hart et al., 1998). NCX1 is one of the ion channels that regulates intracellular Ca2+ transients, which, in turn, modulate signaling pathways, including Ras, directly or indirectly through Ca2+-binding proteins (Iwamoto, 2004) (Fig. 3). Calmodulins (CaM-1, CaM-2, and CaM-3) are the best-characterized Ca2+-binding proteins. Different CaMs are structurally identical, and their functional specificity is likely regulated by differential spatial expression. Interestingly, CaM down-regulates TGF-ß signaling by interacting with Smad1 and Smad2. It also reduces ERK1/2 activation necessary for growth-factor-induced fibroblast proliferation (Zimmerman et al., 1998; Scherer and Graff, 2000; Agell et al., 2002). CaM also phosphorylates CaMKIV, leading to activation of the transcription factor p300/CBP (CREB-binding protein). The p300/CBP acts as a molecular coordinator that regulates the activity of various transcription factors, including AP-1 and Smads (Kamei et al., 1996; Ghosh et al., 2000; Impey et al., 2002; Conkright and Montminy, 2005). For example, p300/CBP enhances Smad-mediated up-regulation of type I collagen expression in fibroblasts (Ghosh et al., 2000). MAPK pathway also potentiates the function of p300/CBP (Janknecht and Nordheim, 1996). Thus, the Sos-Ras-ERK1/2, Smad, and Ca2+ signaling pathways are integrated in fibroblasts and regulate genes that are abnormally expressed in HGF and involved in fibrosis. It is tempting to speculate that perturbation at any level of this signaling cascade, which leads to the increased expression of pro-fibrotic genes, promotes development of gingival overgrowth (Fig. 3). Interestingly, in neurofibromatosis type I, which involves loss-of-function of the neurofibromin that normally down-regulates Ras activation, and in Costello syndrome, which is caused by gain-of-function mutation of H-Ras (a member of the Ras family), some individuals also have gingival overgrowth (Table). Both of these mutations induce activation of the Ras pathway (Bekisz et al., 2000; Hennekam, 2003; Aoki et al., 2005; Scarano et al., 2005; Bentires-Alj et al., 2006). Capillary morphogenetic protein 2 (CMG2), which is mutated in juvenile hyaline fibromatosis, and also involves gingival overgrowth (Sciubba and Niebloom, 1986; Hanks et al., 2003), is a cell membrane, integrin-like molecule that regulates cell adhesion to laminin and type IV collagen (Bell et al., 2001). The signaling pathways regulated by CMG2 are not known in detail, but cell adhesion conveys signals to the SOS-Ras-ERK1/2 pathway, potentially linking CMG2 to the same pathway. Therefore, whether other tissues or only gingiva will be affected likely depends on the importance of each of the mutated genes in the given cells and tissues. |
DIRECTIONS FOR FUTURE RESEARCH |
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TOPABSTRACTINTRODUCTIONCLINICAL PRESENTATIONHISTOLOGICAL CHARACTERISTICSCELLULAR AND MOLECULAR CHANGESGENETIC CHARACTERISTICSSOS-1 GENE MUTATIONPUTATIVE ROLE OF THE...DIRECTIONS FOR FUTURE RESEARCHREFERENCES |
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ACKNOWLEDGMENTS |
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Received February 10, 2006; Accepted June 5, 2006
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