| Abstract|| |
The knowledge and the understanding of the role of growth factors, their mechanisms of action, and molecular signaling pathways, which have been reviewed in this article, suggest the potential for many novel therapeutic targets, not only for applying growth factors but also for the potential use of growth factor inhibitors or agents that target specific parts of the intracellular signaling pathways in controlling oral pathologies. There remains an enormous challenge to convert some of the knowledge from basic studies of bone cell physiology and inflammatory cells to therapeutically useful techniques for the future.
Keywords: Gene therapy, growth factors, IGF, periodontitis, platelet-derived growth factor
|How to cite this article:|
Dabra S, Singh P. A remarkable role of growth factors in resolving oral and specific periodontal pathologies: A strategic review. Indian J Dent Res 2011;22:496-7
Periodontium is a complex organ consisting of soft and mineralized connective tissues which include gingiva, periodontal ligament, cementum, and alveolar bone. There are several diseases which can affect the composition and integrity of periodontal structures. Among these diseases, periodontitis is notable. Periodontitis is characterized by an inflammatory disease of the supporting tissues of the teeth caused by specific microorganisms that leads to the destruction of tooth-associated structures, including cementum, periodontal ligament, and alveolar bone with pocket formation, recession or both. Consequently, if the disease is left untreated, tooth loss can occur. The major goal of periodontal therapy is to arrest disease progression and achieve regeneration of lost tissues. 
|How to cite this URL:|
Dabra S, Singh P. A remarkable role of growth factors in resolving oral and specific periodontal pathologies: A strategic review. Indian J Dent Res [serial online] 2011 [cited 2019 Jul 20];22:496-7. Available from: http://www.ijdr.in/text.asp?2011/22/3/496/87085
Regeneration of periodontal tissue is perhaps one of most complex process to occur in the body as it involves at least six tissue types: The gingival epithelium, gingival connective tissue, periodontal ligament, cementum, alveolar bone, and corresponding vasculature. 
Though the attempt to understand the disease at the cellular and the molecular level through various studies and clinical investigations, in the recent past, has resulted in improved therapies for the arrest of disease progression; there is a need, however, to improve the predictability of regenerative therapies, i.e., the specific cells, growth factors, delivery systems, flap design, and host responses which are required for enhancing the outcome of regenerative therapies should be established. 
Growth factor is a general term used to denote a class of naturally occurring polypeptides which have the potential to alter the host tissue so as to stimulate or regulate the wound-healing process. These growth factors regulate key cellular events in tissue repair, i.e., mitogenesis (proliferation), chemotaxis, differentiation, metabolic activity of cells, and matrix synthesis via binding to specific cell surface receptors.  Thus, it becomes logical to use these molecules to achieve the desired cell population to populate the periodontal space, root, and bone surfaces and result in the synthesis of new bone, cementum, and periodontal ligament. Present studies are directed toward evaluating the effects of growth factors on periodontal regeneration by incorporating growth factors into the controlled release delivery system. Further investigations are required in relation to gene therapy and cell-based therapy where growth factors can help stimulate a particular cell type at particular time and in an established sequence.
| Different Growth Factors|| |
Among various growth factors, PDGF is a potent mitogen, chemotactic agent, and stimulator of protein synthesis for cells of mesenchymal origin. PDGF is stored in the alpha granules of circulating platelets and is released at wound sites during blood clotting; later it may be synthesized locally by infiltrating macrophages. , Insulin-like growth factor (IGF)-I acts in combination with PDGF to promote mitogenesis and protein synthesis in mesenchymal cells in culture. , In previous studies, the topical application of PDGF from human platelets or recombinant IGF-I to partial thickness skin wounds alone did not significantly enhance the repair process, , although when combined, these factors did promote connective tissue and epithelial growth. 
TGF-B stimulates or inhibits the growth of many cell types, depending upon the presence of other growth factors and is a potent chemoattractant for macrophages. ,,, TGF-B is stored in the alpha granules of platelets and synthesized by many cell types in vitro, including macrophages. The addition of TGF-B in vivo increases granulation tissue formation and the tensile strength of healing dermal wounds. , FGF, a polypeptide extracted from the brain, pituitary gland, and other organs stimulates DNA and protein synthesis in mesenchymal and endothelial cells in culture. In vivo FGF promotes angiogenesis and granulation tissue formation. ,, TGF-α is related to EGF and may interact with the same receptors on epithelial cells to stimulate mitogenesis.  Both TGF-α and EGF accelerate re-epithelization of skin wounds.,,,,
| Growth Factors in Dentistry How are They Related?|| |
Growth factors are peptide hormones that have a profound effect on growth. The factors involved in wound healing and regeneration are very much similar to factors that are involved in the formation or the development of tissues. The various events, cells, and proteins currently believed to be involved in regulating the development of periodontal tissues also regulate the regeneration of periodontal tissues.  The dental follicle cells (i.e., the mesenchymal cells surrounding the tooth before root and periodontal development) have the capacity to differentiate into osteoblasts, cementoblasts, or periodontal ligament cells. These are the same cells that are needed for regeneration.
It is also now recognized that specific growth factors and morphogens trigger the differentiation of epithelial and mesenchymal derived cells during tooth formation.  Thus it is reasonable to imagine that many of molecules involved in triggering the development of periodontal tissues may prove to be effective in promoting the regeneration of periodontal tissues. 
| Mode of Action of Growth Factors|| |
The mode of action of the growth factor is the way the growth factor is meant to interact with its target receptor.  The various modes of action of growth factors are as follows:
Endocrine mode of action
The endocrine mode of action is depicted by hormones (contrary to the growth factors) whereby they are secreted by one cell type and travel in the blood stream to a distant target cell to exert their actions. Examples of hormones having this type of action are parathyroid hormone, growth hormone, and luteinizing hormone. ,
Local modes of action are more traditionally associated with the term growth factor and involve paracrine, autocrine, juxtacrine, and intracrine modes. ,
Paracrine mode of action
It involves the production of a factor by one cell and the receptors for the growth factor are present on another cell in the same local micro-environment. The growth factor is secreted by one cell in a soluble manner and binds to receptors on the target (another) cell to evoke its effects, e.g., PDGF and TGF, which are produced by platelets and act on target cells such as lymphocytes and osteoblasts. ,
Autocrine mode of action
It involves the production of the factor by one cell secreted in soluble form outside the cell and then binding to surface receptors on the same cell to evoke an effect, e.g., TGF-α which is produced by and acts on epithelial cells, BMPs which are produced by and act on osteoblastic cells.,
Juxtacrine mode of action
It is similar to the paracrine mode except that the factor produced by cell of origin is cell surface bound and requires cell contact by the target cell to evoke a response, e.g., stem cell factor. 
Intracrine mode of action
It is similar to the autocrine mode in which the factor produced by the cell is not secreted but acts intracellularly to facilitate the effect, e.g., parathormone-related protein (PTHrP) in which a portion of the protein has been shown to translocate to the nucleus to inhibit apoptosis. 
| Receptors for Various Growth Factors|| |
Growth factors are natural cell products; they cannot diffuse across a cell membrane and must act by binding to high-affinity cell receptors.  The receptors are components of the cell membrane which are modified to act in a particular way. For a growth factor to exert its effect, its designated receptor must be present on the cell membrane in sufficient quantity, orientation, and functional activity to transmit the appropriate stimuli. 
Growth factor receptors can be broadly divided into two categories:
The most common prototype of the growth factor receptor is the cell surface receptor. Cell surface receptors commonly bind to peptide factors that are soluble in water but not easily transported across the lipophilic cell membrane.
- Cell surface receptors
- Intracellular receptors.
Cell surface receptors can be further divided into the following:
The intracellular receptors are commonly described for steroids such as
- G-protein-linked receptors
- Platelet-derived growth factor
- Parathormone-related protein
- Receptor tyrosine kinases
- Platelet-derived growth factor
- Insulin-like growth factors I and II
- Fibroblast growth factor
- Serine threonine receptor kinases
- Transforming growth factor β
- Bone morphogenetic proteins.
Steroid receptors have been described in both the cytoplasm and the nucleus of the target cells. Once a cell surface receptor has been bound and activated, a series of second messengers are responsible for evoking a biologic activity. Four main second messengers are as follows:
- Vitamin D3
Protein phosphorylation is a key component of the growth factor activity and is responsible for mediating changes in cell proliferation and cell differentiation which are the hallmarks of the growth factor activity.
- Adenyl cyclase: It is an enzyme activated by G-protein-linked receptors. Adenyl cyclase catalyzes the conversion of ATP to c-AMP, which activates protein kinase A to cause phosphorylation of proteins.
- Phospholipase C: It is also activated by G-protein-linked receptors which causes the activation of protein kinase C to evoke protein phosphorylation.
- Tyrosine kinases and serine threonine receptor kinases: They are also responsible for phosphorylating their target proteins.
| Effect of Growth Factors at Various Levels|| |
The most fundamental process of tissue growth and development begins with cell proliferation. Cells from different tissues grow and divide at quite different rates. Despite this difference, cells undergo a similar pattern of cell division.
There are four main phases of cell cycle: 
For a cell to re-enter the cell cycle from the resting G 0 phase and initiate cell division, a stimulus designated as competence factor is required. One example of competence factor is PDGF. Competence factors are necessary but not sufficient for the cell to enter into the cell cycle. After the cell has been rendered competent to undergo cell division, it requires a progression factor, e.g., IGF-I. Progression factors are sufficient once the cells are rendered competent to progress through the cell cycle, although there are growth factors that may act at later stages to delay or block cells in the G 2 phase. Once a cell has progressed to the S phase, it is committed to undergo cell division. Thus, we can say that growth factors are key regulators of this process of cell proliferation via their action at different stages of the cell cycle. 
- S phase (synthesis phase): DNA synthesis occurs during this phase
- M phase (mitotic Phase): During this phase the cell actually divides
- G 1 and G 2 phase (gap phases): G1 (first gap) and G2 (second gap) between S and M phases
- G 0 phase (resting phase): the cell is at rest; exited from the cell cycle.
Differentiation is a process by which undifferentiated cells transform into a specific type of cell. It is a critical component of tissue regeneration. Differentiation brings about structural and functional changes in the cell which are necessary for the formation of type of tissue, e.g., fibroblast for periodontal ligament, osteoblast for bone, etc. 
Growth factors act in this regard to stimulate or inhibit cell differentiation. These exert their effect through receptor binding and are thus described as regulators of the cell cycle. 
All these findings indicate that growth factors play an important role in the regeneration of periodontal tissues to stimulate the migration, proliferation, and differentiation of various cells that have the capacity to regenerate the tissues. The migration and proliferation of the periodontal ligament fibroblasts and synthesis of the matrix components by the cells are needed for the repair of the periodontal ligament in early phases while the differentiation of the cementoblasts and osteoblasts is needed for the formation of new cementum and new bone in the later phases of the periodontal regeneration. Many of these factors are stored in bone; various growth factors could therefore contribute to the osteoinducive effect of exogenous bone grafts. 
| Future Perspective|| |
In periodontal therapy, different approaches have been developed to treat the disease but the recent ones aim at the regeneration of tissues using biological modifiers, i.e., growth factors. The future prospective lies in use of the knowledge based on molecular and cellular levels using gene therapy, tissue engineering, and cell-based therapy. Changes in gene expression by cells within and adjacent to the wound site can be used to increase the sustainability of the growth factor to the wound site. Future investigations are required to utilize improved delivery systems since most current vehicles used to supply growth factors allow only transient exposure to the periodontal site.
| Delivery of Growth Factors|| |
Various materials which can act as a vehicle for growth factors are described below.
Osseous grafts have been used for decades to treat periodontal defects and are a valuable source of biological mediators (growth factors). Type I collagen gels have been extensively investigated for their space-filling properties as well as for their ability to resorb and release putative biologic mediators in wound-healing situations. Collagen-based sutures and hemostatic sponges have been used extensively in medicine and dentistry. Resorbable collagen barriers have been used clinically for guided tissue regeneration procedures; however, their combination with a biological modifier is yet to be explored. Another area of interest is in synthetic polymer materials, e.g., polyglycolic acid (PGA) and polylactic acid (PLA). Synthetic polymers offer potential for combination with growth factors because they can be prepared reproducibly under controlled conditions. The ability to impregnate these materials with biologically active factors and to control the release of these factors holds great promise for treating periodontal defects.
| Gene Therapy|| |
The term gene therapy originally referred to the treatment of a disease by means of genetic manipulation. According to Strayer, gene therapy may involve 
Much of the initial interest in gene therapy centred on its potential for treating genetic diseases, such as cystic fibrosis and familial hypercholesterolemia. More recently, the potentials for gene therapy have expanded to include gene therapy for defects at local sites (e.g., bone and salivary glands). 
- supplying or increasing the expression of a mutant gene that is insufficiently expressed (e.g., to treat genetic enzymatic deficiencies);
- blocking a gene that is detrimental (e.g., using antisense constructs to inhibit tumor proliferation); or
- adding a foreign gene to treat a situation beyond the capability of the normal genome (e.g., introduce an enzyme into a cell or tissue that allows the tissue to become more sensitive to the effects of a pharmacologic agent).
The single administration of purified tissue growth factor has not been shown to be clinically effective in supporting the horizontal regeneration of the periodontal tissue breakdown. This may be caused by insufficient capabilities to maintain therapeutic protein levels at the wound site and the three-dimensional architecture of the defect. Gene transfer methods may circumvent many of the limitations with protein delivery to soft tissue wounds. The application of growth factors or soluble forms of cytokine receptors by gene transfer provides a greater sustainability than that of a single protein application. Gene therapy may achieve greater bioavailability of growth factors with in periodontal wounds which may provide greater regenerative potential. 
| Gene Delivery Methods|| |
Gene therapy involves the transfer of genetic information to target cells, which enables them to synthesize a protein of interest to treat disease. The technology can be used to treat disorders that result from single point mutations or to increase protein production. The preferred strategy for gene transfer depends on the required duration of protein release and the morphology of the target site. Gene transfer is accomplished through the use of viral and nonviral vectors. Examples of viral vectors are retroviruses, adenoviruses (Ads), and adeno-associated viruses (AAV), and nonviral vectors include plasmids and DNA polymer complexes. ,,
Retroviruses introduce RNA together with two enzymes, called reverse transcriptase and integrase, into the target cell. Initially, the reverse transcriptase enables the production of a DNA copy from the retrovirus RNA molecule. Subsequently, the integrase adds the DNA copy into the target cell DNA. When the genetically altered host cell divides later, its descendants contain the modified DNA. Because the integrase enzyme may insert the DNA copy into an arbitrary position of the target cell DNA, gene disruption and uncontrolled cell division (i.e., cancer) may occur.  Ads contain DNA, which is introduced into the target cell and subsequently transferred into its nucleus. In contrast to the fate of the retrovirus DNA copy, the Ad DNA is not incorporated into the host cell's genetic material. Consequently, when the Ad-infected target cell divides later, its descendants are not genetically altered, nor do they contain the Ad DNA genetic material. AAVs derive from the parvovirus family and are small viruses with a single-stranded DNA genome that cause no known human diseases. AAVs infect dividing and nondividing cells by integrating their genetic material on chromosomes of the target cell. Types of recombinant AAVs have been developed either to remain extra-chromosomal or integrate into nonspecific chromosomal sites. Research has demonstrated that the AAVs can be used to correct genetic defects in animals. One disadvantage of the AAV is that it is small and possesses the capacity to carry no more than usually two genes. ,
Because nonviral alternatives do not have the drawbacks of undesired host immune reactions or potential tumorigenesis, they likely will be given more consideration in the future. Plasmids and DNA polymer complexes carry the genetic information in the form of DNA to express a foreign protein. Design features of the nonviral delivery of DNA match various requirements, such as chromosomal integration or the ability to alter gene expression. 
| Gene Therapy for Periodontal Tissue Engineering|| |
Various gene delivery methods are available to administer growth factors to periodontal defects and offer great flexibility for tissue engineering. The delivery method can be tailored to the specific characteristics of the wound site. For example, a horizontal one or a two-walled defect may require the use of a supportive carrier, such as a scaffold. Other defect sites may be conducive to the use of an Ad vector embedded in a collagen matrix.
More important from a clinical point of view is the risk associated with the use of gene therapy in periodontal tissue engineering.  As with the maximizing growth factor sustainability and accounting for specific characteristics of the wound site, the DNA vector and delivery method must be considered when assessing patient safety. In summary, studies that examine the use of specific delivery methods and DNA vectors in periodontal tissue engineering reflect the aim to maximize the duration of growth factor expression, optimize delivery method to periodontal defect, and minimize patient risk.
Recently, a combination of an AAV-delivered angiogenic molecule such as VEGF, BMP signaling receptor (caALK2), and RANKL (receptor activator of nuclear factor-kappa B ligand) was demonstrated to promote the bone allograft turnover and osteogenesis as a mode to enrich human bone allografts. To date, combinations of VEGF/BMP and PDGF/VEGF have been performed with highly positive synergistic responses in bone repair. ,,
| Preclinical Studies that Evaluate Growth Factor Gene Therapy for Tissue Engineering|| |
To overcome the short half-lives of growth factor peptides in vivo, gene therapy that uses a vector that encodes the growth factor is utilized to simulate tissue regeneration. So far, two main strategies of the gene vector delivery have been applied to periodontal tissue engineering. Gene vectors can be introduced directly to the target site (in vivo technique), or the selected cell can be harvested, expanded, genetically transduced, and then reimplanted (ex vivo technique). ,
In vivo gene transfer involves the insertion of the gene of interest directly into the body anticipating the genetic modification of the target cell. Ex vivo gene transfer includes the incorporation of the genetic material into cells exposed from a tissue biopsy with subsequent reimplantation into the recipient.
| Cell-Based Therapy|| |
Cell-based therapies are most commonly associated with bone marrow transplantation strategies. Bone marrow transplantation has been successfully used to treat a multitude of conditions, including genetic disorders, immune disorders, and tumors. More recently, interest has focused on marrow stromal cells as stem cells for tissues of mesenchymal origin. Hematopoietic stem cells in the bone marrow provide a continuous source of progenitors for blood cells but additionally contain cells that are stem cells for connective tissue. 
Bone marrow stromal cells can differentiate in culture into osteoblasts, chondrocytes, adipocytes, or myoblasts and may also be a more natural source of biologic modifiers in the wound environment. These cells present an intriguing resource for their potential use in periodontal regeneration and are currently being explored on a basic science level.
| Conclusion|| |
Results from various studies clearly indicate that the growth factors have significant influences on cell behavior and they show great promise for use in regenerative therapies. But the regeneration techniques used till date are highly technique sensitive, applicable to limited cases which are susceptible to treatment, and supposed to have relatively low predictability. To overcome these limitations, significant advances have been made to promote the targeted delivery of cells, genes, and proteins to chronic periodontal wounds. With active investigations directed toward understanding the biology of the healing site including identifying appropriate cells to target, coupled with designing delivery systems that can control the release of agents at the local site, using various multidisciplinary approaches combining engineering, dentistry, and medicine, establishing the required environment for the regeneration of periodontal tissues should be feasible.
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MDS, Sr. Lecturer, Department of Periodontology and Oral Implantology, Swami Devi Dyal Hospital and Dental College, Barwala, Panchkula, Haryana
Source of Support: None, Conflict of Interest: None