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Review Multifunctional Roles of Growth Factors Or Biologically Active Peptides in Salivary Glands and Saliva

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Review Multifunctional Roles of Growth Factors Or Biologically Active Peptides in Salivary Glands and Saliva Oral Med Pathol 12 (2008) 115 Review Multifunctional roles of growth factors or biologically active peptides in salivary glands and saliva Masahiko Mori1, Shinichiro Sumitomo1, Prashanta Shrestha2, Shiro Tanaka1, Yoshiaki Takai1, Michio Shikimori1 1Department of Oral-Maxillofacial Surgery, Division of Oral Pathogenesis and Disease Control, Asahi University School of Dentistry, Gifu, Japan 2Division of Oral-Maxillofacial Surgery, Katmandu University Medical School, Katmandu, Nepal Abstract: Salivary glands secrete saliva which contains mucins, antimicrobial substances and growth factors. Since epidermal growth factor (EGF) and nerve growth factor (NGF) were demonstrated in murine submandibular glands (SMGs), several growth factors and biologically-active peptides have been studied in the human or other mammalian salivary glands and saliva. These growth factors may have a functional role in cell migration, proliferation and maturation within not only salivary glands but also other organs. In the SMGs of mice and rats, EGF, NGF and other known growth factors are usually synthesized in granular convoluted tubule cells (GCT). However, human SMGs are devoid of GCT cells, and growth factors in human salivary glands are usually produced in striated ducts. These findings suggest an evolutionary trace of ductal cells in mammals. The present review describes expression patterns of the following salivary gland growth factors: nerve growth factor (NGF); transforming growth factor α and β (TGF-α/β) bone morphogenetic protein (BMP); insulin-like growth factor (IGF); fibroblastic growth factor (FGF); and somatostatin, as well as their receptors. This review also discusses their cell biological roles in pathophysiological conditions. [Oral Med Pathol 2008; 12: 115-123 doi: 10.3353/omp.12.115] Key words: biologically-active peptides, growth factor, growth factor receptor, saliva, salivary gland Correspondence: Michio Shikimori, Department of Oral-Maxillofacial Surgery, Division of Oral Pathogenesis and Disease Control, Asahi University School of Dentistry, Gifu 501-0296, Japan Phone: 81-58-329-1472, Fax: 81-58-329-1472, E-mail: [email protected] shown that a variety of growth factors are also present in the Introduction human salivary glands and saliva. Salivary growth factors Saliva, which is secreted from major and minor salivary have biological functions in cell migration, proliferation and glands, consists of 99% water and 1% organic and inorganic maturation of not only oral but also other tissues after they components, including sodium, potassium, chloride, calcium, are absorbed from the digestive tract mucosa. Many of these phosphates and bicarbonates (1). The major components of growth factors may function directly or indirectly in the salivary organic molecules are mucins, carbohydrate maintenance and stimulation of salivary gland tissues as complexes, enzymes, anti-microbial peptides and growth well as in distant organs by autocrine or paracrine manners factors or biologically active peptides. Since the detection of (2). nerve growth factor (NGF) and epidermal growth factor The present review deals with biological and (EGF) in murine submandibular glands, considerable physiological roles of such growth factors produced in advances have been made in understanding the functional salivary glands as nerve growth factor (NGF), transforming role of these growth factors or biologically active peptides, factors α and β, bone morphogenetic protein (BMP), and they are at present a major field of study in cell biology vascular endothelial growth factor (VEGF), insulin-like and oral health sciences (2). growth factor (IGF), fibroblast growth factor (FGF), and Initially, EGF and NGF were reported to be biosynthesized stomatostatin, as well as their receptors. In addition, gene in granular convoluted tubule (GCT) cells of submandibular expression modes of these growth factors are summarized in ducts and secreted in the saliva of mice, and studies have salivary glands and their lesions. 116 Mori et al. Growth factors in salivary glands yet fully differentiated in neonatal SMGs. The levels of both 1. Nerve growth factor (NGF) and epidermal growth factors are increased with maturation, with the growth factor (EGF) highest levels in puberty and gradually declining with age Biosynthesis of NGF as well as EGF in granular (22). NGF and EGF in the murine SMGs were dramatically convoluted tubule (GCT) cells has been reported in the lowered by duct ligation. In testosterone-treated mice, mouse submandibular gland (SMG), and their expression in lowering levels of both growth factors were induced by duct GCT cells is increased following administration of thyroid ligation (23-24). Experimentally-induced carcinoma in hormone and testosterone. The levels of both of these growth murine SMGs was shown to be associated with decreasing factors are shown to be male-hormone dependent, and expression levels of NGF and EGF in duct-like structures, expression of both growth factors in the male SMG is whose epithelial cells were supposed to be responsible for stronger than those in the female gland. Secretion of EGF the tumorigenesis of squamous cell carcinoma (25). In and NGF in the SMG could be controlled by similar cellular pleomorphic adenoma, mRNA for NGF receptor (NGFR) or molecular events, and they function in cell migration, has been reported to be overexpressed (26). differentiation and repair processes (3). Ekstrom and Reinbold (27) recently reported that the The surgical removal of murine adult SMG has been concentration of NGF was five times higher in the parotid shown to cause a significant reduction in plasma and tissue gland than in the SMG of adult female rats. Unilateral concentration of NGF and reduced tyrosine hydroxyease sympathetic denervation of the superior cervical ganglion activity levels in sympathetic ganglions (4). Concentration results in elevated levels and concentrations of NGF in the of serum NGF, however, was not necessarily different SMG, but not in the parotid glands 7-28 days after the between males and females, and the serum NGF level does operation. It is thus suggested that increased levels of NGF not change by removal of SMG (5). Murine 7S NGF from play a role in the activity of choline acetyltransferase, one of the saliva contains more α-submits than that from the SMG the acetylcholine-synthesising enzymes, in rat SMGs. In (6). Salivary NGF discharge is changed by secretagous head and neck surgery, sympathetic denervation may elevate treatments: concentrations of mouse NGF in epinephrine- or activity levels of such enzymes, which may also be norepinephrine-induced saliva (3400 μg/ml and 900 μg/ml, associated with an increased production of NGF. respectively) are higher than in other sources, while the concentrations of NGF in isoproterenol- and pilocarpine- 2. Transforming growth factor-α and -β (TGF-α, induced saliva are relatively low (17 and 2 μg/ml, TGF-β) respectively) (7). NGF secreted from the mouse SMG enters into blood stream within minutes and reaches the highest TGF-α and TGF-β have distinct functional roles. TGF-α level 3-4 hrs later (8). It has been reported that cyclocytidine is biosynthesed by a large variety of cells, such as (Cyclo-C) treatments in mice resulted in an increased NGF keratinocytes, hepatocytes, gastrointestinal cells, and cells level in the serum, that chronic Cyclo-C stimulation of the brain and placenta (28), whereas the biosynthesis of produces an increase in the volume of sympathetic ganglia TGF-β is done in platelets, macrophages, lymphocytes, and neuronal hypertrophy, and that Cyclo-C produces a fibroblasts and keratinocytes (29). TGF-α, a member of the drastic depletion of NGF in GCT cells of the mouse SMG as EGF family, binds with EGF receptors on the cell membrane well as a marked NGF level increase in the bloodstream (9). to exert its biological activities. BMPs are members of the Lipps (10), by using high pressure liquid chromatography, TGF-β superfamily. The TGF-β family consists of TGF-1, 2, found that the molecular weights of human NGF in serum, and 3 and BMPs 1-6, and these TGFs are synthesized by saliva and urine were identical, at 36.0 kDa molecules, while mesenchymal cells including bone cells and osteoprogenitor those of cobra serum and cobra venom were 55.0 kDa and cells. The following paragraphs describe biological and 13.5 kDa, respectively. physiological functions of both TGF-α and -β in salivary Immunohistochemical studies on NGF as well as EGF in glands. SMGs of mice and rats showed sexual dimorphism (8). Expression of TGF-α has been reported in a wide variety Olson et al. (11) described that NGF was immunolocalized of cells in the digestive tract including salivary glands (30). in the apical zone of GCT cells as well as cells responsible TGF-α mRNA has been demonstrated in the salivary and for spermatogenesis in male mice. NGF has been shown to mammary glands (31). TGF-α is also present in human adult be colocalized with EGF, rennin, and protease A in murine saliva (32). Ogbureke et al. (33) have reported TGF-α SMGs (12). The coexistence of NGF and EGF has also been immunolocalization in the human ductal cells in salivary reported (13-14). There are some other reports demonstrating glands, but acinar and myoepithelial cells are unreactive. similar tissue distributions of NGF (15) α and g units of Whole salivary fluids from rat, mouse, and human have been 7S-NGF (16) in mouse SMG. In-situ hybridization for NGF demonstrated to contain a high concentration of TGF-α by mRNA revealed that GCT cells in male mouse SMGs as well using radioimmunoassay. TGF-α in unstimulated human as ductal cells in sublingual glands were responsible for saliva is reduced with age (55-70 yrs. 0.4 ± 0.1 nM) but NGF production (17-18). Similar results were obtained in increased in xerostomia (57-70 yrs, 0.8 ± 0.2 nM) and the prostate gland of the guinea pig (19-21). Paget's disease (58-70 yrs, 0.8 ± 0.2 nM).
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