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Year : 2006  |  Volume : 9  |  Issue : 2  |  Page : 78-80
Emerging role of the insulin like growth factors in pulp healing, reparative dentinogenesis and periodontal regeneration


Department of Periodontics, Meenakshi Ammal Dental College and Hospital, Chennai, India

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   Abstract 

The role of Insulin like growth factors (IGF) in neoplastic transformation, in transversion of cell cycle during the growth and development by induction of enamel biomineralisation of the tooth and in periodontal development have been well documented in the past. However studies suggesting its usage in dental therapy have been limited. This review article hence, brings together various studies that have suggested its role as a therapeutic agent in dental pulp healing and reparative dentinogenesis along with periodontal regeneration. Positive results were achieved when IGF was combined with other therapeutic agents like platelet derived growth factor (PDGF) and calcium hydroxide in healing of apical perforations. When combined with heparin. IGF-l increased the expression of bone morphogenic protein 4 mRNA. Treatment with IGF-I inhibited DNA fragmentation in periodontal ligament fibroblasts. This article also includes background information on the IGF system and its mechanism of action.

How to cite this article:
Sudhakar U, Ramakrishnan, Anand P B. Emerging role of the insulin like growth factors in pulp healing, reparative dentinogenesis and periodontal regeneration. J Conserv Dent 2006;9:78-80

How to cite this URL:
Sudhakar U, Ramakrishnan, Anand P B. Emerging role of the insulin like growth factors in pulp healing, reparative dentinogenesis and periodontal regeneration. J Conserv Dent [serial online] 2006 [cited 2020 Oct 30];9:78-80. Available from: https://www.jcd.org.in/text.asp?2006/9/2/78/42362

   Introduction Top


During the past decade there has been a concerted effort in the field of molecular and cell biology to understand the mechanism of growth factors on the repair and regeneration of tissues. Polypeptide growth factors are a class of natural biological mediators, which regulate critical cellular events involved in wound healing, they also regulate the growth and development of variety of organs. Growth factors elicit their effects by binding to specific cell surface receptors with transducer signals to the cell nucleus via various signal transduction pathways. Insulin like growth factors are a family of growth factors, receptors and binding proteins that are not only involved in various processes of growth and differentiation but also in numerous pathological conditions. Insulin like growth factors (IGFs) are single chain polypeptides targeting receptors on the cell surface. The activity of IGF is modulated by specific IGF binding protein, IGF may be of great value in treating periodontal defects [1] .

The IGF System

Insulin like growth factors (IGF) includes 3 ligands Insulin, IGF-I and IGF-l1. These cell surface receptors arc Insulin, IGF-I and IGF-II, (Mannose-6-phosphate) receptors. Six high affinity IGF binding proteins (IGFBPs), which bind the circulating IGFs and modulate the biological actions. They also contain additional receptors such as Insulin receptor-related receptor, Insulin-IGF I hybrid receptor and growing number of IGFBPs-related proteins [1] .

The Role of IGF-I

The IGF were initially identified as liver derived sulfation factors shown to mediate the effect of growth hormone. (Somatotropin) (Salmon & Davghadog 1957) [2] .

(a) The original somatomedin hypothesis suggested that the effects of GH on postnatal growth were mediated by somatomedin (now known as IGF-I), which was thought to be derived from the liver and secreted into the circulation.

(b) The hypothesis was later revised to include evidence that most, if not all, tissues produced 1GF-I, and that GH affected circulating levels of liver-derived IGF-I, as well as the stability of circulating IGF-I, via the IGFBP-3ALS complex. In addition, GH was capable of influencing local tissue production of IGF-I, thereby maintaining its overall control on postnatal growth.

(c) The most recent studies have suggested that, at least in mice, liver-derived IGF-I is not essential for postnatal growth and development. However, many questions remain to be answered regarding the importance of circulating IGF-I.

Mechanism of Action of lGF

Insulin and insulin-like growth factors are highly homologous growth hormones, which initiate the biological response in a wide variety of cells by binding to their specific cell surface receptors. IGFs induce autophosphorylation of the receptors through intrinsic tyrokinase activity. The increase in tyrosine kinase activity leads to a cascade of phosphorylation events, which are necessary to generate the intracellular second messenger signal required for biological cellular response [3] .

The Role of the JGF System in Tooth Growth and Development

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 biomineralisation (Gotz 2001) [4] .

Immunohistochemical analysis of IGF system in human deciduous teeth revealed that odontoblasts do not express IGFs or the IGF-IR, but contain IGFBPs and IGF-IIR Gotz et al 2001) [4] . Cementoblasts and periodontal ligament fibroblasts express the IGF-IR.

During tooth development IGF functions in a paracrine or autocrine function. IGF-l and IGF-IR are synthesized locally by tooth forming cells. The onset of enamel secretion is accompanied by a strong hybridization signal in the secretary ameloblasts as well as in the odontoblasts [5] .

Role of IGF in Pulp Healing and Reparative Dentinogenesis

Several animal experiments have shown the influence of IGF-I in the process of dental pulp healing and in reparative dentinogenesis. Pulp capping of rat molars by means of IGF-I enhanced reparative dentinogenesis (Lovschall et al 2001) [7] (B.Rutherford 1995) [8] . The activity of IGF-I is modulated by specific IGF binding proteins. Application of IGF-I with heparin increased the expression of bone morphogenetic protein 4 mRNA in isolated dental papilla from mice (Hu, Czhang et al 1998) [9] . When IGF-I combined with platelet derived growth factor (PDGF) was added to calcium hydroxide, there was significant improvement in healing of apical perforations in dogs. Moreover there was no inflammatory reaction in the apical tissues and the connective tissue adjacent to the newly formed hard tissues was strongly immunostained for osteonectin (Kim et al 2001) [6] . Recently the influence of IGF-II has been studied invivo. The influence of growth factors on dentin formation remains to be elucidated [7] . IGF-I could get trapped in the dentin matrix structure during its synthesis, secretion and mineralization and could be released into dental pulp after an injury to the pulpodentin complex, stimulating repair process. Miri Kim, Byunhyun Kim, [6] in their animal study, used PDGF-BB and IGF-l with calcium hydroxide for apical perforation in dog premolars. It resulted in good apical bone regeneration, enhanced healing, minimal inflammation and apical cementum deposition.

The Role of IGF System in Periodontal Structures

IGF-I has been suggested to prevent apoptosis in fibroblasts. IGF-I treatment inhibited DNA fragmentation in periodontal ligament fibroblasts.

Antiapoptic effects of IGF-1 require activation of phosphoionositole 3-kinase (pi3k) which leads of the phosphorylation and activation to downstream signaling molecule, protein kinase B (PKB) which in turn leads to phosphorylation and inactivation of pro - apoptic receptor [10] .

These members can function either to suppress or promote cell death by controlling apoptosis associated mitochondrial events like the release of cytochrome C into the cytosol, and the activation of the primary apoptotic DNA fragmentation.

Periodontal ligament fibroblasts respond to IGF-I more strongly than gingival fibroblasts and this differential response to IGF-I could stem from the tissue specificity of these cells within the periodontium by IGF.

Periodontal Tissue Engineering by IGF

A clinical trial to evaluate a combination of recombinant human PDGF and recombinant human IGF- I in patients with periodontal disease was conducted (W.V.Giannobile 1996) [11] . It was found that the product was safe and a single application of PDGF/ IGF- I resulted in significant improvement in bone growth and fill of periodontal defects. IGF- I had been shown to synergistically increase osteoblast mitogenesis in cultured bone cells when combined with other growth factors such as bFGF, PDGF or TGF Enamel matrix derivative when used with IGF increased the periodontal ligament fibroblasts attachment (D.B.Palioto et al) [12] .


   Conclusion Top


IGF system clearly plays a major role in normal and pathological oral processes. IGFs are involved not only in biology of several periodontal structures but also in tooth growth and development including accumulation of many enamel-specific gene products involved in induction of enamel biomineralization. IGF-I has been shown to be chemotactic for cells derived from PDL and has strong effects on PDL cell mitogenesis and protein synthesis. Both IGF-I and IGF-II are found in large amounts in bone, with IGF-II more abundant in bone matrix. IGF-I produced by osteoblasts stimulates bone formation by inducing cellular proliferation, differentiation and type I collagen biosynthesis. Increasing experimental evidence supports the notion that IGFs in combination with other growth factors help in dental pulp healing, reparative dentinogenesis and also augment the osseous healing process (D.Tziajas 2004) [13] . Use of tools like growth factor delivery system (GFDS) for tissue engineering of mineralized oral structure may provide future clinicians with additional options for treatment of substantially damaged or diseased vital teeth (M.Dard 2000) [14] . 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 its potential interactions with other hormones and growth factors [15] .

 
   References Top

1.H. Werner and J. Katz: The Emerging Role of the Insulin Like Growth Factors in Oral Biology. J. Dent Res 83(11): 832-836,2004  Back to cited text no. 1    
2.Salmon, Davghadog : What is the Role of Circulating IGF-1. Trends in Endocrinology and Metabolism Vo112 No.2, March 2001  Back to cited text no. 2    
3.Christensen GJ: Pulp Capping. J. Am Dent Assoc 129:1297-1299,1998  Back to cited text no. 3    
4.Gotz W, Kruger U: lmmunohistochemical Localization of Components of the Insulin-like Growth Factor System in Human Deciduous Teeth. Connective Tissue Research, 42: 291 302, 2001.  Back to cited text no. 4    
5.Javier Caviedcs-Bucheli, Hugo Roberto Munoz: Expression of IGF-1 Receptor In Human Pulp Tissue. Journal of endodontics, vol.30, No.11, Nov 2004.  Back to cited text no. 5    
6.Miri Kim Byunghyun: Effect on the Healing of Periapical Perforations in Dogs of the addition of Growth Factors to Calcium Hydroxide. Journal of Endodontics, Vol. 27,No. 12, Dec 2001.  Back to cited text no. 6    
7.H. Lovschall, O. Fejerskov: Pulp-capping with Recombinant Human Insulin-like Growth Factor I (rhIGF-I) in Rat Molars. Adv Dent Res 15: 108 112, Aug 2001.  Back to cited text no. 7    
8.B.Rutherford, M.Fitzgerald: A new biological approach to vital pulp therapy. Critical review in oral biology and medicine vol.6,218-229,1995.  Back to cited text no. 8    
9.Hu, Czhang, Q.Qian: Reparative dentinal formation in rat molars after direct pulp capping with growth factors. J Endodontic 1998.  Back to cited text no. 9    
10.Han, S. Amar: IGF-I Signaling Enhances Cell Survival in Periodontal Ligament Fibroblast vs. Gingival Fibroblast. J Dent Res 82(6): 454 459. 2003.  Back to cited text no. 10    
11.W.V. Giannobile: Periodontal Tissue Engineering by Growth Factors. Bone Vol. 19, No. 1,235-375, July 1996.  Back to cited text no. 11    
12.D.B.Palioto: Enamel matrix derivative associated with IGF-1 on periodontal ligament fibroblasts. Adv Den Res 2000.  Back to cited text no. 12    
13.D.Tziajas: The future role of molecular approach to pulp dentinal regenaration. Caries Research 2004.  Back to cited text no. 13    
14.M.Dard, A.Sauraj, J.Meyer:Tool for tissue engineering of mineralized oral structures. J Clinical Oral Investigation Vol 4, No 2, Jun 2000.  Back to cited text no. 14    
15.B.Futher fierd: Transplantation of human pulpal and gingival fibroblast attached to synthetic scaffolds. EurJ Oral Sci 1999.  Back to cited text no. 15    

Top
Correspondence Address:
Uma Sudhakar
Department of Periodontics, Meenakshi Ammal Dental College and Hospital, Chennai
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0972-0707.42362

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