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The Emerging Role of the Insulin-like Growth Factors in Oral Biology

¹ Department of Clinical Biochemistry, Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel; and
² Division of Oral Medicine, Department of Oral/Maxillofacial Surgery and Diagnostic Sciences, University of Florida College of Dentistry, PO Box 100416, Gainesville, FL 32610-0416, USA;

^* corresponding author, jkatz{at}dental.ufl.edu

	ABSTRACT

TOP ABSTRACT THE IGF SYSTEM ENDOCRINE vs. LOCAL ACTIONS... THE CELLULAR ROLE OF... IGFS AND CANCER THE ROLE OF THE... THE ROLE OF THE... THE ROLE OF THE... PATHOLOGICAL ASPECTS SUMMARY REFERENCES

 
The insulin-like growth factors (IGF) are a family of growth factors, receptors and binding proteins that are involved in numerous growth and differentiation processes, as well as in various pathological conditions. The aim of this review is to summarize data that has been accumulating in recent years linking the IGF system to a number of physiological and pathological oral processes. The IGF system fulfills an important role in growth and development of teeth, mandible, maxillae, and tongue. It has been postulated that IGF-I may be of great value in the treatment of periodontal defects and in tissue healing. Furthermore, IGF-II has been shown to be overexpressed in salivary gland adenomas, suggesting that aberrant IGF signaling may be a key factor in the etiology of oral malignancies. Understanding the role and regulation of IGF system components in salivary glands and other oral structures will be of significant basic and clinical relevance.

KEY WORDS: insulin-like growth factors (IGF) • IGF-I receptor • oral biology • salivary gland • Sjögren’s syndrome

	THE IGF SYSTEM

TOP ABSTRACT THE IGF SYSTEM ENDOCRINE vs. LOCAL ACTIONS... THE CELLULAR ROLE OF... IGFS AND CANCER THE ROLE OF THE... THE ROLE OF THE... THE ROLE OF THE... PATHOLOGICAL ASPECTS SUMMARY REFERENCES

 
The insulin-like growth factors (IGFs) are a family of mitogenic proteins that control growth, differentiation, and the maintenance of differentiated function in numerous tissues. The IGF family includes 3 ligands (insulin, IGF-I, and IGF-II), 3 cell-surface receptors (the insulin, IGF-I, and IGF-II/mannose 6-phosphate receptors), and at least 6 high-affinity IGF-binding proteins (IGFBPs), which bind circulating IGFs and modulate their biological actions (Fig.). In addition to these "classic" family members, more recent work has identified several other proteins as potential components of the IGF system. These "non-classic" members include 2 additional receptors (the insulin receptor-related receptor and the insulin-IGF-I hybrid receptor) and a growing number of IGFBPs-related proteins. The aim of this Concise Review is to summarize data that have been accumulating over the last 15 years regarding the involvement of the IGF system in normal and pathological oral processes. Special emphasis will be placed on the emerging role of the IGF system in the biology of the salivary gland and periodontium. In addition, evidence will be provided linking the IGF system with specific types of oral cancer.

View larger version (23K): [in this window] [in a new window]   Figure. The IGF system. The IGF system is comprised of 3 ligands (insulin, IGF-I, and IGF-II), 3 receptors (insulin, IGF-I, and IGF-II/mannose 6-phosphate receptors), and at least 6 IGF-binding proteins (IGFBP1-6). Naturally occurring hybrid receptors have been described in which an insulin /ß hemireceptor is linked to an IGF-I /ß hemireceptor. The black area in the receptor cytoplasmic region denotes the tyrosine kinase domain. The IGF-II/mannose 6-phosphate receptor is a single-chain polypeptide composed of 15 repeat sequences and a short cytoplasmic domain. IGF-I and IGF-II circulate in blood and extracellular space linked to a family of binding proteins. IGFBP3 is the most abundant BP in serum, and it appears as a ternary complex that includes the ligand and an acid-labile subunit (ALS). IGFBP proteases have been described that cleave IGFBPs, thus modulating the bioavailability of IGF ligands. IGFBP6 exhibits a particularly high affinity for IGF-II.

	ENDOCRINE vs. LOCAL ACTIONS OF IGF FAMILY MEMBERS

TOP ABSTRACT THE IGF SYSTEM ENDOCRINE vs. LOCAL ACTIONS... THE CELLULAR ROLE OF... IGFS AND CANCER THE ROLE OF THE... THE ROLE OF THE... THE ROLE OF THE... PATHOLOGICAL ASPECTS SUMMARY REFERENCES

	THE CELLULAR ROLE OF IGF-I

TOP ABSTRACT THE IGF SYSTEM ENDOCRINE vs. LOCAL ACTIONS... THE CELLULAR ROLE OF... IGFS AND CANCER THE ROLE OF THE... THE ROLE OF THE... THE ROLE OF THE... PATHOLOGICAL ASPECTS SUMMARY REFERENCES

 
At the cellular level, IGF-I is an important progression factor that is required for the entire cell cycle to be traversed. Overexpression of IGF-I and the IGF-IR in fibroblasts abrogated the requirement for additional growth factors and allowed the cells to grow in serum-deprived medium, thus suggesting that an intact IGF-I-IGF-IR axis is sufficient to elicit the growth response (Werner and LeRoith, 1997).

One of the most important aspects of IGF-I action that allow the peptide to function as a cell survival agent is its strong anti-apoptotic activity. The capacity of IGF-I to inhibit apoptotic death has been demonstrated in multiple cellular systems, including cerebellar granule neurons, pheochromocytoma cells, hemopoietic and erythroid colony-forming cells, etc. (D’Mello et al., 1993; Muta and Krantz, 1993). The critical determinant for cell survival proved to be the number of cell-surface IGF-IRs. The obvious implication of these findings is that activation of the IGF-IR may rescue from apoptosis cell populations that, in the absence of IGFs, are tagged for elimination.

	IGFS AND CANCER

TOP ABSTRACT THE IGF SYSTEM ENDOCRINE vs. LOCAL ACTIONS... THE CELLULAR ROLE OF... IGFS AND CANCER THE ROLE OF THE... THE ROLE OF THE... THE ROLE OF THE... PATHOLOGICAL ASPECTS SUMMARY REFERENCES

 
In addition to its important role in normal growth, it is now well-established that the IGF system has a fundamental role in malignant transformation (Werner and LeRoith, 1996). This notion is supported by both clinical and experimental evidence, including the widespread observation that ligands and receptors are usually overexpressed by most primary tumors and transformed cell lines (Mitsiades et al., 2004). Moreover, IGF-IR-null fibroblasts cannot be transformed by any of several oncogenes, including the SV40 large T-antigen, activated ras, and the bovine papillomavirus E5 protein (Morrione et al., 1995).

The transforming potential of the IGF-IR is further illustrated by the results of experiments demonstrating that receptor overexpression in NIH3T3 cells resulted in a ligand-dependent, highly transformed phenotype (Kaleko et al., 1990). As a corollary to the important role of the IGF-IR in malignant transformation, several experimental protocols have been designed to target the IGF-IR as a potential therapeutic approach. These methodologies include the use of peptide analogues of IGF-I, antireceptor antibodies, antisense oligonucleotides, small interference RNA, and several chemical compounds, including specific tyrosine kinase inhibitors (Bohula et al., 2003; Mitsiades et al., 2004).

The central role of the IGF system in the initiation and progression of cancer is further highlighted by the finding that IGF-I constitutes a risk factor in several malignancies, including breast, prostate, lung, and colorectal cancer (Pollak, 2000).

	THE ROLE OF THE IGF SYSTEM IN GROWTH REGULATION OF SALIVARY GLAND CELLS

TOP ABSTRACT THE IGF SYSTEM ENDOCRINE vs. LOCAL ACTIONS... THE CELLULAR ROLE OF... IGFS AND CANCER THE ROLE OF THE... THE ROLE OF THE... THE ROLE OF THE... PATHOLOGICAL ASPECTS SUMMARY REFERENCES

 
Early studies have identified IGF-I and IGF-II, but not IGFBPs, in human saliva (Costigan et al., 1988). Salivary IGF-I levels were significantly lower in GH-deficient patients, whereas substantially higher IGF-I values were measured in acromegalic patients, suggesting that IGF-I concentrations in saliva reflect the GH status of the patient (Halimi et al., 1994). Salivary IGF-I measurements were 100- to 200-fold lower than plasma values (Ryan et al., 1992a). However, the developmental pattern of expression was similar to that in plasma, i.e., low IGF-I levels in childhood that rise with age, peak in puberty, and fall again in late adolescence. To assess the origin of salivary IGF-I, investigators have administered ¹²⁵I-IGF-I intracardially into rats, followed by gel chromatography and SDS-PAGE analyses of plasma and saliva samples (Ryan et al., 1992b). Results obtained showed that IGF-I was unable to cross from the plasma pool through to saliva, suggesting that IGF-I in saliva is produced locally (Amano and Iseki, 1993). In situ hybridization revealed that IGF-I mRNA was localized primarily in the granular convoluted tubule cells of the gland (Kerr et al., 1995). Evidence that a functional insulin/IGF signaling pathway is present in salivary glands was provided by studies showing that insulin and IGF-I receptors are present in the gland, and that insulin treatment induced a dose-dependent phosphorylation of both receptors, as well as phosphorylation of the downstream substrates insulin receptor substrate (IRS)-1 and -2 and Shc (Rocha et al., 2000).

The effects of several growth factors and cytokines on the regulation of IGF system components in salivary-gland-derived cells were recently investigated by means of the HSG cell line. Treatment of HSG cells with tumor necrosis factor- (TNF-) and interferon- (IFN-) induced a significant decrease in cellular proliferation that was associated with increased accumulation of IGFBP-3 (Katz et al., 1995). When antibodies to IGFBP-3 were used in conjunction with TNF- and IFN-, the inhibitory effects of the cytokines on cell growth were diminished (Katz et al., 1999). Analysis of these data supports the hypothesis that inhibitory growth factors and cytokines may exert their biological actions, at least in part, via specific induction of IGFBP-3 and, potentially, other BPs. As a result of the increment in IGFBP levels, IGF-I is able to shift from the free to the IGFBP-3-bound form, with ensuing reduction in IGF-I-mediated mitogenic action.

In addition, the inhibitory effects of TNF- and IFN- on HSG cell proliferation were associated with a significant decrease in IGF-IR mRNA and protein levels, and with inhibition of IGF-IR promoter activity, suggesting that both cytokines affect IGF-IR gene expression at the transcriptional level (Shalita-Chesner et al., 2001).

	THE ROLE OF THE IGF SYSTEM IN TOOTH GROWTH AND DEVELOPMENT

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Using mandibular first molars in primary culture, investigators have demonstrated that IGF-I induced the accumulation of several enamel-specific gene products, including amelogenin and ameloblastin, suggesting that the IGF system is involved in the induction of enamel biomineralization (Takahashi et al., 1998). Immunohistochemical analysis of IGF system components in human deciduous teeth revealed that odontoclasts do not express IGFs or the IGF-IR, but do contain IGFBPs and the IGF-IIR (Gotz et al., 2001). These results suggest that odontoclasts, in contrast to osteoclasts, may not respond to IGFs, but are probably involved in the release and sequestration of IGFs from cementum during the resorption process. In contrast to odontoclasts, cementoblasts and periodontal ligament fibroblasts express the IGF-IR.

The concept that IGF-I functions in a paracrine/autocrine fashion during tooth development has been demonstrated by immunohistochemistry and in situ hybridization methods (Joseph et al., 1996). IGF-I and IGF-IR were shown to be synthesized locally by tooth-forming cells. The distribution and intensity of the hybridization signal, however, varied with the developmental stage of the rat incisor. Thus, the cells of the apical loop expressed a positive hybridization signal, but the earliest polarized odontoblasts and pre-ameloblasts did not show any positive signal. The onset of enamel secretion was accompanied by a strong hybridization signal in the secretory ameloblasts as well as in the odontoblasts. The cells of the pulp and the dental follicle were consistently negative. However, in the adjacent alveolar bone, there was a strong signal in osteoblasts and osteoclasts.

The role of IGF-I in pulp healing and reparative dentinogenesis following pulp-capping was recently investigated (Lovschall et al., 2001). For this purpose, exposures were made through the mesial pulp horn in first upper molars in several two-month-old Wistar rats. The pulp was covered with methylcellulose gel containing or lacking IGF-I (400 ng). The exposure site was closed. After 3, 7, or 28 days, molars were decalcified and processed for histological analysis. Results obtained indicate that pulp-capping of rat molars by means of IGF-I enhanced reparative dentinogenesis in comparison with vehicle-treated controls. Furthermore, the effect of IGF-I addition, in combination with platelet-derived growth factor (PDGF), to calcium hydroxide in the repair of apical perforations was recently evaluated in a canine model (Kim et al., 2001). Fifty-one premolar teeth from 4 beagle dogs were used in this study. After periapical lesions developed, root apices were artificially perforated, following which the teeth were divided into 3 groups: (1) The apical perforations were not sealed; (2) the perforated areas were obturated with calcium hydroxide; and (3) sites of perforation were sealed with calcium hydroxide plus growth factors. After 12 wks, teeth were stained with hematoxylin/eosin and osteonectin. Analysis of the results showed that, in group 3, there was no inflammatory reaction of apical tissue, and the connective tissue adjacent to the newly formed hard tissue was strongly immunostained for osteonectin. In comparison, most sections in group 1 showed no apical healing, whereas moderate healing was found in group 2. Thus, these results demonstrate that the combination of IGF-I and PDGF with calcium hydroxide significantly improved healing of apical perforations in dogs.

	THE ROLE OF THE IGF SYSTEM IN PERIODONTAL STRUCTURES

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As mentioned above, the IGF system has a fundamental role in protecting cells from programmed cell death. In the particular context of the periodontium, IGF signaling has been shown to induce strong anti-apoptotic activity, as illustrated by the fact that IGF-I treatment inhibited DNA fragmentation in periodontal ligament fibroblasts, compared with gingival fibroblasts, during serum deprivation (Han and Amar, 2003a). This effect of IGF-I was associated with up-regulation of several anti-apoptotic molecules and down-regulation of several pro-apoptotic molecules (Han and Amar, 2003b).

Increasing experimental evidence supports the notion that IGF-I may be of great importance in periodontal regeneration. Two commonly used animal models for the evaluation of putative periodontal regenerative therapies are the beagle dog model with natural periodontal disease and the non-human primate with ligature-induced attachment loss. The results of experiments comparing the healing responses to periodontal surgery with and without concurrent use of IGF-I and PDGF showed that, at 1 mo, IGF-I/PDGF administration resulted in 64% and 51% increase in new attachment formation in the primate and canine models, respectively (Giannobile et al., 1994). In comparison, control animals (surgery plus placebo) demonstrated 34% and 8% increases, respectively, in new attachment formation in either model. Likewise, enhanced regeneration of both the soft and hard components of the periodontium following PDGF and IGF-I administration in beagle dogs has been reported (Lynch et al., 1991). Taken together, combined IGF-I/PDGF treatment appears to be of significant value in promoting periodontal wound healing.

	PATHOLOGICAL ASPECTS

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In addition to its role in normal growth and differentiation processes, the IGF system is involved in several pathological oral processes. Results of an immunohistochemical study performed on labial salivary glands of Sjögren’s syndrome patients, healthy controls, and patients with mucoceles of the lip revealed the presence of a mononuclear infiltration in glands of Sjögren’s patients associated with a strong immunohistochemical staining. In contrast, sections of labial salivary glands of healthy individuals and of patients with mucoceles revealed very weak IGF-I immunoreactivity. The fact that both lymphocytic infiltration and IGF-I were predominantly seen in ductal regions suggests that IGF-I may be a target of autoimmunity in Sjögren’s syndrome (Markopoulos et al., 2000). Immunohistochemical analysis of insulin receptor and IGF-IR expression in the minor salivary glands of Sjögren’s syndrome patients indicated that insulin receptor expression was increased in the patients, while IGF-IR levels were higher in the controls (Katz et al., 2003).

To investigate the mechanisms of tissue destruction in experimental autoimmune sialadenitis (EAS), an animal model of Sjögren’s syndrome, investigators assessed the expression of the IGF-IR in the submandibular glands of an NOD mouse with this disease (Mustafa et al., 2001). Receptor-binding autoradiography revealed that IGF-IR levels in submandibular glands were significantly reduced in NOD mice with EAS. Diminished IGF-IR levels may induce a defective glandular homeostasis in the submandibular gland epithelial cells and may thus trigger EAS.

The involvement of IGF-II in the etiology of salivary gland adenoma was inferred from studies showing that IGF-II transcripts are highly expressed in adenomas overexpressing PLAG1 (Voz et al., 2000). PLAG1 is a zinc finger gene that undergoes re-arrangement in pleomorphic adenoma of the gland with 8q12 translocations. In contrast, IGF-II transcripts are not detectable in adenomas without abnormal PLAG1 expression, or in normal salivary gland tissue. Hence, these results suggest that IGF-II is one of the PLAG1 target genes. Transcriptional activation of the IGF-II gene by PLAG1 may constitute an important mechanism in the initiation and/or progression of salivary gland tumors. Further support for a potential role of the IGF system in oral squamous cell carcinoma was recently provided by the results of a study showing that genetic variation at the IGF-II receptor locus may influence cancer risk (Zavras et al., 2003).

	SUMMARY

TOP ABSTRACT THE IGF SYSTEM ENDOCRINE vs. LOCAL ACTIONS... THE CELLULAR ROLE OF... IGFS AND CANCER THE ROLE OF THE... THE ROLE OF THE... THE ROLE OF THE... PATHOLOGICAL ASPECTS SUMMARY REFERENCES

 
The IGF system of ligands, receptors, and binding proteins is clearly a major player in normal and pathological oral processes. IGFs are involved both in tooth growth and development as well as in the biology of several periodontal structures. Furthermore, IGFs regulate various aspects of salivary gland homeostasis. The recent recognition that IGF-I may be of potential clinical relevance in oral pathologies will significantly enhance both basic and clinical IGF research. Among other issues still to be resolved are the precise molecular mechanisms responsible for the regulatory roles of the IGF system in the specific context of oral biology, and the potential interactions of the IGF system with other signaling systems, including the extracellular matrix and other hormones and growth factors.

Received January 21, 2004; Last revision August 27, 2004; Accepted August 31, 2004

	REFERENCES

TOP ABSTRACT THE IGF SYSTEM ENDOCRINE vs. LOCAL ACTIONS... THE CELLULAR ROLE OF... IGFS AND CANCER THE ROLE OF THE... THE ROLE OF THE... THE ROLE OF THE... PATHOLOGICAL ASPECTS SUMMARY REFERENCES

 
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