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Hereditary Gingival Fibromatosis: Characteristics and Novel Putative Pathogenic Mechanisms
L. Häkkinen* and
A. Csiszar
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;
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Figure 1. Clinical (A,B) and histological (C–F) characteristics of hereditary gingival fibromatosis (B,D,F), as compared with healthy gingiva (A,C,E). Clinical picture of gingiva from a young healthy adult (A) and from a 7-year-old patient with hereditary gingival fibromatosis (HGF) (B). (C,D) Hematoxylin and eosin staining. In HGF, epithelium is thickened and displays narrow, elongated rete pegs that penetrate deep into the connective tissue (D), while in normal marginal gingiva, the epithelium is thin and rete pegs are shorter (C). In addition, cell density in the connective tissue in HGF appears lower (D) as compared with normal tissue (C). Hematoxylin- and eosin-stained samples examined under a microscope equipped with a UV light source and rhodamine filter are shown in E and F. Typical basket-weave organization of collagen is noted in the normal gingiva (E), while in HGF, collagen is organized into thick parallel fiber bundles (F). Fig. 1B was kindly provided by Dr. Hannu Larjava, University of British Columbia, Vancouver, Canada. E, epithelium; CT, connective tissue. Magnification bar, 50 µm.
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Figure 2. Function, structure, and expression of SOS-1 in human gingiva. (A) Schematic representation of the major intracellular signaling pathways regulated by SOS-1. In unstimulated cells, SOS-1 associates preferentially with the adaptor molecule Grb2. Binding of a growth factor to its receptor induces autophosphorylation of the growth factor receptor’s cytoplasmic tail. The SOS-1/Grb2 complex is translocated to the activated receptor, where it associates with Ras and promotes formation of GTP from GDP and activates Ras. Activated Ras induces phosphorylation of ERK1/2 of the mitogen-activated protein kinase (MAPK) pathway that regulates various key cell functions. The activated MAPK can phosphorylate SOS-1, leading to dissociation of the SOS-1/Grb2 complex (dashed lines). In the stimulated state, SOS-1 can also form a complex with the adaptor molecules E3b1 and Eps8 instead of Grb2. Formation of this trimolecular complex is not affected by phosphorylation of SOS-1 by the MAPK pathway. The trimolecular complex promotes association of SOS-1 with the small GTPase Rac and causes Rac activation by inducing nucleotide exchange from GDP to GTP. Activated Rac regulates re-organization of cytoskeletal actin and the cell functions that are regulated by this process. The activation of Ras by growth factors is usually short-lived, while the activation of Rac is sustained. (B) Structural comparison of the wild-type and mutant SOS-1 present in HGF1. SOS-1 is a multidomain protein. Together, the DH (Dbl homology) domain and the PH (pleckstrin homology) domain are involved in the activation of Rac. The Ras exchanger motif (Rem) domain and the Cdc25 domain are both needed for the interaction with Ras. The last C-terminal domain contains several proline-rich motifs that serve as a docking site for the src homology 3 (SH3) domain present in the adaptor molecules Grb2 and E3b1. In HGF1, there is a single cytosine insertion at codon 1083 (proline) in exon 21 that results in a frame-shift mutation and an early termination of the protein. The mutant protein also has a 22-amino-acid missense addition at the C-terminus. (C) Expression of SOS-1 in human gingiva. SOS-1 was immunolocalized in healthy human marginal gingiva with a polyclonal antibody against SOS-1 (Santa Cruz Biotechnology Inc., Santa Cruz, CA, USA), with the ABC avidin-peroxidase reagent (Vectastain Elite kit, Vector Laboratories Inc., Burlingame, CA, USA) and the VIP substrate (Vector Laboratories Inc.). SOS-1 localizes in the basal and spinous layers of the epithelium and in connective tissue cells (a). In the connective tissue, SOS-1 is expressed by blood vessels (arrowheads) and fibroblasts (arrows) (b). In the rete ridges of the epithelium, the strongest expression of SOS-1 localizes in the cytoplasm of the basal cells (c). In the connective tissue papilla area, the strongest immunoreactivity for SOS-1 localizes at the basal cell membrane, facing the basement membrane (d; arrowheads). A set of representative tissue sections from five different individuals is shown. E, epithelium; CT, connective tissue. Magnification bar = 50 µm.
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Figure 3. Simplified model of integration between the Ca2+ and SOS-Ras-ERK1/2 and Smad signaling pathways as a putative mechanism for gingival overgrowth. As a response to, e.g., growth factor stimulation, intracellular Ca2+-ion concentration can locally increase as a result of the release of Ca2+ from intracellular stores (endoplasmic reticulum or mitochondria), or by changes in the function of cell-membrane ion pumps (e.g., NCX1) that regulate Ca2+ influx and efflux. Local Ca2+ transients can induce SOS-1/Grb2-mediated activation of Ras, leading to phosphorylation and activation of downstream signaling pathways, including ERK1/2 of the MAPK pathway. Ca2+ can also bind to calmodulin (CaM), and this complex down-regulates Ras-mediated ERK1/2 activation and the TGF-β-regulated Smad pathway in fibroblasts. CaM/Ca2+ can also induce activation of Ras and calmodulin-dependent protein kinases (CaMKs), including CaMKIV. Neurofibromin (NF) accelerates inactivation of GTP-bound Ras. Activation of the TGF-β-receptor by TGF-β activates the Smad and Ras-ERK1/2 pathways. At the transcriptional level, CaMKIV through p300/CBP (CREB-binding protein), ERK1/2 through AP-1 (activating protein-1), and Smads collaborate to regulate pro-fibrotic gene expression and cell proliferation in fibroblasts.
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Journal of Dental Research, Vol. 86, No. 1,
25-34 (2007)
DOI: 10.1177/154405910708600104
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