Table of Contents  
Year : 2016  |  Volume : 8  |  Issue : 1  |  Page : 12-15

Fibronectin in periodontal health and disease

1 Department of Periodontics, Sathyabama University Dental College and Hospital, Chennai, Tamil Nadu, India
2 Department of Periodontics, Priyadarshini Dental College, Chennai, Tamil Nadu, India

Date of Web Publication6-May-2016

Correspondence Address:
Dr. Sumathi H Rao
Flat 4F, Block A, Phase II, Tranquil Acres, 200 Ft MMRD Road, Kovilambakkam, Chennai - 600 117, Tamil Nadu
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/0975-8844.181918

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Fibronectin is a main component of connective tissue and has various biologically significant roles to play in tissue integrity, remodelling and repair, apart from influencing pathological processes. This review looks into the physiology of fibronectin and its influences in health and disease.

Keywords: Attachment, collagen, fibrin, fibroblasts, fibronectin

How to cite this article:
Manimegalai A G, Rao SH, Ravindran D. Fibronectin in periodontal health and disease. J Orofac Sci 2016;8:12-5

How to cite this URL:
Manimegalai A G, Rao SH, Ravindran D. Fibronectin in periodontal health and disease. J Orofac Sci [serial online] 2016 [cited 2023 Jun 9];8:12-5. Available from:

  Introduction Top

Fibronectin is a main component of the noncollagenous proteins that form the ground substance of tissues. It is a high-molecular weight (~440 kDa) glycoprotein that exists as a protein dimer, consisting of two nearly identical monomers linked by a pair of disulfide bonds. Its other names are cold-insoluble globulin, α2 -surface binding opsonic protein, antigelatin factor, large external transformation-sensitive protein, and cell surface protein. [1]

Two types of fibronectin are present in vertebrates:

  • Soluble plasma fibronectin (formerly called "cold-insoluble globulin" of CIg) is a major protein component of blood plasma (300 μg/ml) and is produced in the liver by hepatocytes.
  • Insoluble cellular fibronectin is a major component of the extracellular matrix. It is secreted by various cells, primarily fibroblasts, as a soluble protein dimer and is then assembled into an insoluble matrix in a complex cell-mediated process. [2]

Keratinocytes have been shown to produce soluble fibronectin in vitro. [1],[3],[4] It binds to the membrane-spanning receptor proteins - integrins. Similar to integrins, fibronectin binds extracellular matrix components such as collagen, fibrin, and heparin sulfate proteoglycans.

Fibronectin is necessary for embryogenesis, and inactivating the gene for fibronectin results in early embryonic lethality. Fibronectin plays a major role during embryonic development by guiding cell attachment and migration. In mammalian development, the absence of fibronectin leads to defects in mesodermal, neural tube, and vascular development. Similarly, the absence of a normal fibronectin matrix in developing amphibians causes defects in mesodermal patterning and inhibits gastrulation. [1] Thus, it can be stated that fibronectin plays a major role in the formation of the periodontal apparatus.

  Fibronectin in Health Top

Both collagen and fibronectin are essential components of the vertebrate extracellular matrix. This lies in the fact that they interact directly with cellular receptors and affect cell adhesion and migration. [5] Fibronectin forms fibrils in the extracellular matrix and interacts with denatured collagen (gelatin) or isolated collagen chains, preferentially to unwound collagen. The proposed binding site for fibronectin on collagen I coincides with the cleavage site for metalloproteinase-1 that is, the collagenase site. Hence, fibronectin binding may be protective in nature. [6]

Fibronectin has a wide variety of functional activities besides binding to cell surfaces through integrins. It binds to a number of biologically important molecules that include heparin, collagen, gelatin, and fibrin. These interactions are mediated by several distinct structural and functional domains, which have been defined by proteolytic fragmentation or recombinant DNA analyses. [4],[7],[8]

Fibronectin is also found in normal human saliva and is said to have a protective role by preventing colonization of the oral cavity and pharynx by potentially pathogenic bacteria.

  Fibronectin in Inflammation and Wound Healing Top

Fibronectin contains two major heparin-binding domains that interact with heparin sulphate proteoglycans. In at least some cell types, the heparin-binding domains of fibronectin potentiate cell adhesion. [4],[7]

Fibronectin also contains two major fibrin binding sites (fibrin I and fibrin II). The major site is in the N-terminal domain and is formed by type I repeats 4 and 5. The interaction of fibronectin with fibrin is thought to be important for cell adhesion or cell migration into fibrin clots. This interaction may also be involved in macrophage clearance of fibrin from circulation after trauma or in inflammation. [4],[7]

During the course of the inflammatory periodontal disease, host-derived proteases cleave the extracellular matrix and release fragments of it, including fibronectin fragments, into the inflammatory milieu. The presence of specific fibronectin fragments (of 40, 68, and 120 kDa) in gingival crevicular fluid is a marker of periodontal disease status. Furthermore, these 40 and 120 kDa fragments produced by chymotrypsin cleavage induce apoptosis or suppress osteoblast differentiation of periodontal ligament cells. The mechanisms by which this proteolytic signature of fibronectin fragments is generated in periodontal disease, including the relative contributions of bacterial and host-derived proteases have to be investigated further. [9]

Fibronectin plays a crucial role in wound healing. Along with fibrin, plasma fibronectin is deposited at the site of injury, forming a blood clot that stops bleeding and protects the underlying tissue. During clotting of the plasma the fibronectin remains associated with the clot, covalently cross linked to the fibrin with the help of factor XIII (fibrin stabilizing factor). Patients with factor XIII deficiencies display impairment in wound healing and also that the fibroblasts don't grow in the fibrin which is deficient in this factor. Plasma fibronectin levels are decreased in acute inflammation or following surgical trauma and in patients with disseminated intravascular coagulation. [10]

Fibroblasts secrete proteases, including matrix metalloproteinases that digest the plasma fibronectin, and then the fibroblasts secrete cellular fibronectin and assemble it into an insoluble matrix. Fragmentation of fibronectin by proteases has been suggested to promote wound contraction, a critical step in wound healing. Fragmenting fibronectin further exposes its V-region, which contains the site for α 4 β 1 integrin-binding. These fragments of fibronectin are believed to enhance α 4 β 1 integrins expressing cell binding, allowing them to adhere to and forcefully contract the surrounding matrix. Fibronectin also promotes phagocytosis of particles, not only by macrophages but also by fibroblasts. Macrophages have been shown to readily phagocytose denatured collagen when they are coated with fibronectin, thus aiding in remodelling. [10]

  Fibronectin in Gingival Overgrowths Top

Fibronectin location differs in various drug-influenced gingival enlargements. A study investigated the distribution of fibronectin in the healthy, inflamed and hyperplastic human gingiva by indirect immunofluorescence. Fibronectin appeared as a fibrillar structure in the lamina propria of the healthy gingivae. In inflamed tissue, it demonstrated parallel fibres, especially in the coronal areas of the tissue. In the phenytoin gingival overgrowth, tissue fibronectin was observed as thin fibres with variable length. The thin fibres gave the appearance of penetrating the basement membrane of the epithelium. Cyclosporin A gingival enlargement could be differentiated by phenytoin lesions because of the higher length and the parallel distribution of fibronectin. Finally, fibronectin was observed in the nifedipine gingival overgrowth, where a delicate microfibrillar network gave the appearance of a "cloud"- a pattern of distribution. In all of the specimens, blood vessels and nerves could not be stained. [11]

Phenytoin-induced overgrowth tissues contain higher levels of fibronectin in connective tissue fibroblasts in both sub-sulcular and sub-oral regions underlying the epithelium. The spliced form of fibronectin, often elevated in fibrotic tissues is present at significantly higher levels in phenytoin samples. [12]

Gingival biopsy samples taken from patients on nifedipine, cyclosporine or a combination of the two showed that expression of certain integrins was up-regulated in the epithelium of drug-induced gingival overgrowth with increased expression in the cellular extra domain A of fibronectin. The authors proposed that this increased expression of fibronectin along with integrins could participate in controlling the formation of elongated rete ridges and tissue fibrosis. [13]

Gingival samples taken from patients with hereditary gingival fibromatosis show increased proliferation and elevated production of type I collagen and fibronectin. This could contribute to the clinically seen enlargement. [14]

  Fibronectin in Carcinoma Top

Extracellular matrix molecules influence differentiation, proliferation, migration, and have stabilizing and separating functions. Onco-fetal fibronectin has been found in the basement membranes of oral squamous cell carcinomas. [10] The extent of basement membrane defects correlates with invasive and metastatic potential. The malignant cells may come into contact with the abundant stromal fibronectin matrix through these defects and can spread along fibronectin zones.

Several of the morphological changes observed in tumors and tumor-derived cell lines have been attributed to decreased fibronectin expression, increased fibronectin degradation, and/or decreased expression of fibronectin-binding receptors, such as α5β1 integrins. In lung carcinoma, fibronectin expression is increased, especially in nonsmall cell lung carcinoma. The adhesion of lung carcinoma cells to fibronectin enhances tumorogenicity and confers resistance to apoptosis-inducing chemotherapeutic agents. Fibronectin has been shown to stimulate the gonadal steroids that interact with vertebrate androgen receptors, which are capable of controlling the expression of cyclin D and related genes involved in cell cycle control. These observations suggest that fibronectin may promote lung tumor growth/survival and resistance to therapy, and it could represent a novel target for the development of new anticancer drugs. [15] Fibronectin-1 acts as a potential biomarker for radio resistance, which is the property of organisms that are capable of living in environments with very high levels of ionizing radiation. [16]

  Fibronectin in Periodontal Therapy Top

Fibronectin is available as part of a commercial Fibrin Glue System (Tisseel ® ). [17] Studies have shown that Fibronectin aids in early attachment and healing of surgical wounds when compared to GTR, but results were statistically not significant. [17],[18],[19],[20] It is however, not widely used in periodontal therapy as compared to oral surgical use, mainly due to the cost factor and availability of wider and better range of materials and systems.

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Conflicts of interest

There are no conflicts of interest.

  References Top

Mosher DF, Furcht LT. Fibronectin: Review of its structure and possible functions. J Invest Dermatol 1981;77:175-80.  Back to cited text no. 1
Baum BJ, Wright WE. Demonstration of fibronectin as a major extracellular protein of human gingival fibroblasts. J Dent Res 1980;59:631-7.  Back to cited text no. 2
O′Keefe EJ, Woodley D, Castillo G, Russell N, Payne RE Jr. Production of soluble and cell-associated fibronectin by cultured keratinocytes. J Invest Dermatol 1984;82:150-5.  Back to cited text no. 3
Pankov R, Yamada KM. Fibronectin at a glance. J Cell Sci 2002;115(Pt 20):3861-3.  Back to cited text no. 4
Erat MC, Schwarz-Linek U, Pickford AR, Farndale RW, Campbell ID, Vakonakis I. Implications for collagen binding from the crystallographic structure of fibronectin 6FnI1-2FnII7FnI. J Biol Chem 2010;285:33764-70.  Back to cited text no. 5
Fields GB. A model for interstitial collagen catabolism by mammalian collagenases. J Theor Biol 1991;153:585-602.  Back to cited text no. 6
Katagiri Y, Brew SA, Ingham KC. All six modules of the gelatin-binding domain of fibronectin are required for full affinity. J Biol Chem 2003;278:11897-902.  Back to cited text no. 7
Erat MC, Sladek B, Campbell ID, Vakonakis I. Structural analysis of collagen type I interactions with human fibronectin reveals a cooperative binding mode. J Biol Chem 2013;288:17441-50.  Back to cited text no. 8
Sönmez S, Canda T, Ozkara E, Ak D. Quantitative evaluation of the vasculature and fibronectin localization in gingival connective tissue of smokers and non-smokers. J Periodontol 2003;74:822-30.  Back to cited text no. 9
Grinnel F, Billingham RE, Burgess L. Distribution of Fibronectin in Wound Healing In Vivo. J Inves Dermatol 1981;76:181-9.  Back to cited text no. 10
Romanos GE, Schröter-Kermani C, Hinz N, Bernimoulin JP. Distribution of fibronectin in healthy, inflamed and drug-induced gingival hyperplasia. J Oral Pathol Med 1992;21:256-60.  Back to cited text no. 11
Sume SS, Kantarci A, Lee A, Hasturk H, Trackman PC. Epithelial to mesenchymal transition in gingival overgrowth. Am J Pathol 2010;177:208-18.  Back to cited text no. 12
Walsh P, Häkkinen L, Pernu H, Knuuttila M, Larjava H. Expression of fibronectin-binding integrins in gingival epithelium in drug-induced gingival overgrowth. J Periodontal Res 2007;42:144-51.  Back to cited text no. 13
Tipton DA, Howell KJ, Dabbous MK. Increased proliferation, collagen, and fibronectin production by hereditary gingival fibromatosis fibroblasts. J Periodontol 1997;68:524-30.  Back to cited text no. 14
Kosmehl H, Berndt A, Strassburger S, Borsi L, Rousselle P, Mandel U, et al. Distribution of laminin and fibronectin isoforms in oral mucosa and oral squamous cell carcinoma. Br J Cancer 1999;81:1071-9.  Back to cited text no. 15
Jerhammar F, Ceder R, Garvin S, Grénman R, Grafström RC, Roberg K. Fibronectin 1 is a potential biomarker for radioresistance in head and neck squamous cell carcinoma. Cancer Biol Ther 2010;10:1244-51.  Back to cited text no. 16
Manimegalai AG. A comparative study on the efficacy of a commercial fibrin adhesive (Tisseel) vis-à-vis silk suture on wound closure following periodontal surgical procedures. J Indian Soc Periodontol 2010;14:231-5.  Back to cited text no. 17
[PUBMED]  Medknow Journal  
Caffesse RG, Nasjleti CE, Anderson GB, Lopatin DE, Smith BA, Morrison EC. Periodontal healing following guided tissue regeneration with citric acid and fibronectin application. J Periodontol 1991;62:21-9.  Back to cited text no. 18
Stavropoulos A, Karring T. Five-year results of guided tissue regeneration in combination with deproteinized bovine bone (Bio-Oss) in the treatment of intrabony periodontal defects: A case series report. Clin Oral Investig 2005;9:271-7.  Back to cited text no. 19
Palachur D, Prabhakara Rao KV, Murthy KR, Kishore DT, Reddy MN, Bhupathi A. A comparative evaluation of bovine-derived xenograft (Bio-Oss Collagen) and type I collagen membrane (Bio-Gide) with bovine-derived xenograft (Bio-Oss Collagen) and fibrin fibronectin sealing system (TISSEEL) in the treatment of intrabony defects: A clinico-radiographic study. J Indian Soc Periodontol 2014;18:336-43.  Back to cited text no. 20
[PUBMED]  Medknow Journal  

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