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Concise Review: Saliva and Growth Factors: The Fountain of Youth Resides in Us All
T. Zelles, K.R. Purushotham, S.P. Macauley, G.E. Oxford and M.G. Humphreys-Beher J DENT RES 1995 74: 1826 DOI: 10.1177/00220345950740120301 The online version of this article can be found at: http://jdr.sagepub.com/content/74/12/1826
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Concise Review
Abstract. The predominant focus of research dealing with saliva revolves around the role in the maintenance of oral health through a number of physiological and biological properties of constituent proteins. An ever-expanding literature exists indicating that the salivary glands additionally synthesize, and secrete into saliva, a wide range of growth factors. Animal studies with epidermal growth factor have provided evidence for a role in both oral and systemic health, through the promotion of wound healing rates. Thus, the ability to manipulate their rates of synthesis and absorption from saliva holds the potential to enhance tissue regeneration and homeostasis.
Introduction
Salivary constituents carry out a number of biological functions which are key to maintaining oral health. In fact, the component proteins, produced and released into the saliva by the salivary glands, are grouped according to their functions. These proteins aid in lubrication of the oral cavity (mucins, proline-rich proteins), remineralization (statherin, anionic proline-rich proteins), and digestion (amylase, lipase, proteases), as well as provide antimicrobial activity (proline-rich proteins, lysozyme, histatins, lactoperoxidase), and maintain mucosal integrity (water, mucins) (Herrera et al., 1988; Fox, 1989). However, missing from this last category, and in general discussions about saliva composition, is the incredibly rich source of growth factors that are present in saliva and their synthesis by the salivary glands. The healing properties of saliva were recognized as far back as 2000 years ago by the ancient Greeks, who applied snake saliva to open wounds to enhance cutaneous wound healing (Angeletti et al., 1992). It was the identification of epidermal growth factor from mouse submandibular glands (Levi-Montalcini and Cohen, 1960; Cohen, 1962) and its subsequent characterization that were recognized by the Nobel Award Committee for Medicine and Physiology in 1986. There is a large variety of polypeptides in saliva whose functions, in part, remain unknown. In addition, there are large gaps in the level of understanding of the properties of those growth factors that have been identified. These biologically active proteins include epidermal growth factor (EGF) and nerve growth factor (NGF), which are synthesized and secreted by the granular convoluted tubule cells (Barka, 1980; Gresik, 1980; Watson et al., 1985; Gresik, 1994). However, this short list of biologically active peptides produced by the salivary glands and released into saliva has grown significantly since the late 1980s to include transforming growth factor-alpha (TGF-oL: Yeh et al., 1989; Humphreys-Beher et al., 1994), insulin (Murakami et al., 1982; Smith and Patel, 1984; Kerr et al., 1995), insulin-like
Key words: salivary glands, epidermal growth factor, saliva, wound healing.
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growth factors I and II (IGF-I, IGF-II: Costigan et al., 1988; Ryan et al., 1992; Kerr et al., 1995), transforming growth factor-beta (TGF-P: Amano et al., 1991; Jaskoll et al., 1994), and fibroblast growth factor (FGF: Hiramatsu et al., 1994). These growth factors have been identified, for the most part, in animal and human saliva and animal salivary glands.
mice typically secreting a 100-fold higher level of growth factor into saliva than female mice (Byyny et al., 1974; Gubits et al., 1986). On the other hand, serum levels of EGF are similar in both sexes (Olsen et al., 1984; Kurachi and Oka, 1985). Genetic models of insulin-dependent diabetes mellitus as well as chemically induced diabetes have been shown to decrease the level of synthesis and thus lower saliva concentrations of EGF and NGF (Kasayama and Oka, 1989; Hu et al., 1992; Serrero et al., 1993). The decline of EGF synthesis in the salivary glands in diabetes could explain the poor rates of wound healing in this condition. Because diabetic animals develop peripheral neuropathy similar to that in humans, and NGF is known to promote sympathetic and sensory neuron development (Robertson and Sima, 1980; Scott et al., 1983), by analogy, these studies further suggest that the decreased production of NGF by the submandibular gland could potentially be involved in the pathogenesis observed in diabetic neuropathy (Kasayama and Oka, 1989).
are
reduced as a consequence of lower EGF levels caused by sialoadenectomy (Kurachi et al., 1985; Yamamoto et al., 1994).
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and placenta (Derynck, 1988). TGF-ao shares structural similarity with EGF, and is a member of the EGF-like growth factor family. As such, it binds to the EGF receptor to exert its biological properties. The growth factor is synthesized by the ductal cells of the parotid and submandibular glands in rodents; however, unlike EGF, there is no evidence for a sexual dimorphism of its expression (Humphreys-Beher et al., 1994). The role of TGF-a- in maintaining epithelial cell growth and implication in wound healing are evidenced by transgenic mice in which TGF-a is overexpressed and subsequently causes epithelial cell hyperplasia in a number of organ systems (Vasser and Fuchs, 1991). Overexpression of TGF-ac and gastrin in the pancreas using an insulin promoter markedly increased duct cell metaplasia (Wang et al., 1993). Null mutants of TGF-a in transgenic mice, while appearing healthy and fertile, showed physical and histological alterations in skin, coat, and corneal formation (Mann et al., 1993).
et al., 1994a,b).
The detection of insulin in the parotid and submandibular glands and recognition of its synthesis by immunoassay and immunohistochemistry have been controversial (Carter et al., 1995). The apparent structure of salivary insulin is identical to that of pancreatic insulin. This has given rise to speculation that the source of insulin in saliva is the pancreatic islets, with blood transport responsible for its presence in the salivary glands and saliva. However, the presence of insulin mRNA and incorporation of radiolabeled amino acids into immunoprecipitable insulin in in vitro cultured parotid gland slices led to the conclusion of active synthesis of insulin by the salivary glands (Murakami et al., 1982; Kerr et al., 1995).
Insulin and the insulin-like growth factor family (IGF-I and IGF-II)
Insulin-like growth factors I and II have substantial amino acid sequence homology to pro-insulin (Baxter, 1986). Both IGFs are synthesized as large precursor molecules which are proteolytically cleaved to release the biologically active monomer. While pro-insulin requires further processing to remove the C-peptide for generation of biologically active insulin, IGF-I and IGF-IJ retain this segment, which is required for biological activity. The activities of insulin, IGFI, and IGF-II are modulated by specific binding proteins present in serum (Dai et al., 1994). Insulin-like growth factors I and II are synthesized in a wide variety of adult tissues, with IGF-I synthesis primarily occurring in the liver, heart, lung, kidney, and brain. IGF-II synthesis occurs predominantly during fetal development and in tumor cells of the liver (Rogler et al., 1994). The duct cells of the submandibular and parotid glands of mice and rats synthesize both IGF-I and IGF-II (Kerr et al., 1995). Both IGF-I and IGF-II have been isolated from human saliva (Costigan et al., 1988). Transgenic mice overexpressing IGFII develop hypoglycemia and hypoinsulinemia. IGF-I is a potent regulator of oligodendrocyte development in the brain and myelination of the central nervous system (McMorris et al., 1993). Transgenic mice overexpressing IGFI demonstrate the capacity of IGF-I to regulate brain growth (D'Ercole, 1993).
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and keratinocytes. The BMPs were originally identified by their presence in bone-inductive extracts (Butler et al., 1977). BMPs can induce cartilage and bone formation through osteoblast differentiation when implanted ectopically into rats (Wozney et al., 1990). High levels of expression for BMPs have been reported in developing fetal tissues, including limb buds, hair, heart, and teeth, leading to the suggestion of a critical role in morphogenesis that appears to be a characteristic of the TGF-19 super-family (Lyons et al., 1990). While saliva-derived EGF may be cytoprotective against gastrointestinal tract ulceration by promoting mucosal epithelial cell replacement, purified recombinant TGF-fl has been shown to suppress growth of certain cancer cell lines in vitro. Human colon cancer subsets have recently been identified with defects in mismatch repair genes that lead to a specific loss of the type II TGF-fg receptor. This strengthens the argument for a potential role for TGF-I in regulating normal colon cell function (Markowitz et al., 1995). Thus, it is not unrealistic to speculate that salivaderived TGF-1 may be important in maintaining overall health of the digestive tract.
The oral application of growth factors such as EGF for the treatment of gastric ulcers has been proposed based upon the ease of ingestion and direct delivery (Itoh et al., 1988). While growth factors in general demonstrate acid-resistant degradation, oral delivery is still subject to problems of accurate dosing. Uptake through the gastrointestinal tract leads to a short half-life, principally due to portal vein release into the hepatic system (Covelli et al., 1972; Kim et al., 1988). Alternatively, administration of polypeptide hormones has been investigated for rectal, vaginal, buccal, nasal, ocular, and transdermal uptake and dissemination (Fisher, 1923; Anders et al., 1983; Chiou and Chuang, 1988).
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systemic diseases, thus maximizing the use of this regenerative fluid within us all.
Acknowledgments
This work was supported by NIDR grant DE 08778 to MHB, DE 10234 to KRP, and the Health Science Council grant T-02 352/93 and the Hungarian National Foundation for Scientific Research (OTKA) No. 1083 to TZ. GEO and SPM are supported by the Oral Biology Training Grant DE 07200.
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