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Year : 2012  |  Volume : 8  |  Issue : 2  |  Page : 199-203

Pathogenesis of oral submucous fibrosis

Department of Oral Medicine and Radiology, Yenepoya Dental College, Yenepoya University, Deralakatte, Mangalore, Karnataka, India

Date of Web Publication26-Jul-2012

Correspondence Address:
Saba Khan
Department of Oral Medicine and Radiology, Yenepoya Dental College, Yenepoya University, Deralakatte, Mangalore - 575018, Karnataka
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/0973-1482.98970

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 > Abstract 

Data from recent epidemiological studies provide overwhelming evidence that areca nut is the main etiological factor for oral submucous fibrosis (OSF). It is logical to hypothesize that the increased collagen synthesis or reduced collagen degradation is the possible mechanism in the development of the disease. There are numerous biological pathways involved in the above processes and it is likely that the normal regulatory mechanisms are either down regulated or up regulated at different stages of the disease. The copper content of areca nut is high and the possible role of copper as a mediator of fibrosis is supported by the demonstration of the up regulation of lysyl oxidase in OSMF biopsies. The aim of this article is to emphasize that the incorporation of copper into the areca nut is through the Bordeaux mixture, which is sprayed as a fungicide on areca plantations in regions with scheduled monsoons and of which copper sulfate is an important constituent.

Keywords: Areca nut, arecoline, cytokines, oral submucous fibrosis, pathogenesis

How to cite this article:
Khan S, Chatra L, Prashanth SK, Veena K M, Rao PK. Pathogenesis of oral submucous fibrosis. J Can Res Ther 2012;8:199-203

How to cite this URL:
Khan S, Chatra L, Prashanth SK, Veena K M, Rao PK. Pathogenesis of oral submucous fibrosis. J Can Res Ther [serial online] 2012 [cited 2022 Aug 17];8:199-203. Available from: https://www.cancerjournal.net/text.asp?2012/8/2/199/98970

 > Introduction Top

Oral submucous fibrosis (OSF), first described in the early 1950s, is a potentially malignant disease predominantly seen in people of Asian descent. It is a chronic progressive disorder and its clinical presentation depends on the stage of the disease at the time of detection. The majority of patients present with an intolerance to spicy food, rigidity of lip, tongue and palate leading to varying degrees of limitation of mouth opening and tongue movement.

The hallmark of the disease is submucosal fibrosis that affects most of the parts of oral cavity, pharynx and upper third of the esophagus. The factors that have been discussed as possible etiological factors to date are areca nut, capsaicin in chillies, micronutrient deficiencies of iron, zinc and essential vitamins. In addition, a possible autoimmune basis to the disease with demonstration of various auto-antibodies and an association with specific HLA antigens has been proposed. [1]

The association between copper and OSF has been linked on the basis that excess copper is found in tissues of other fibrotic disorders- Wilson's disease, Indian childhood cirrhosis and primary biliary cirrhosis. [1] The nature and characteristics of copper compound in areca nut is unknown yet. The solubility of these complexes in physiologic solutions such as saliva has not been fully evaluated, but preliminary findings have shown that soluble copper is extracted into the saliva during the chewing of areca products. [2]

 > Areca Alkaloids Causing Fibroblast Proliferation Top

Among the areca alkaloids such as arecoline, arecadine, guvacoline, guvacine, arecoline is the main agent responsible for fibroblast proliferation. Under the influence of slaked lime (Ca(OH) 2 ), arecoline get hydrolyzed to arecadine, which has pronounced effects on fibroblasts. [1] A study by Harvey et al showed that exposures to 0.1-10 μg/ml arecoline stimulates fibroblasts and concentrations more than 25 μg/ ml, inhibits fibroblast growth and collagen synthesis. [3] Jeng et al found that depletion of cellular glutathione (GTH) levels by arecoline predisposes the oral mucosal fibroblasts to various genotoxic and cytotoxic stimulation. [4]

 > Clonal Selection of OSF Fibroblasts by Arecoline Top

Studies have shown that arecoline causes elevated collagen synthesis by OSMF fibroblasts compared to normal fibroblast. This could reflect clonal selection of a cell population in altered tissues under the influence of local factors such as IL-1 from inflammatory cells. [5]

 > Stablization of Collagen Structure by Tanins and Catachins Top

Areca flavonoids tannins and catechins can cause increased fibrosis by forming a more stable and non soluble collagen structure by inhibiting collagenase enzyme activity. [6] Studies have shown that there is 1.5 fold increase in collagen production by OSMF fibroblasts and with the progression of disease type 3 collagen is completely replaced by type 1 collagen which is more resistant to degradation. [7] Also there has been an excess of alpha 1 (1) chains relative to alpha 2(1) chains, suggesting an alteration of collagen molecule during the disease progression. [8] Recently a study done on human buccal fibroblasts showed an increased expression of an insoluble cytoskeleton protein (57kDa) called vimentin in OSMF patients under arecoline influence. This protein vimentin is primarily expressed by mesenchymal cells, during cell growth, and tumorigenesis. Thus elevated vimentin expression stimulated by arecoline in OSMF may be suggestive of transformational changes in buccal fibroblasts of OSMF patients. [9]

 > Inhibition of Collagen Phagocytosis Top

According to studies, there is a gross imbalance in the extracellular matrix remodeling in OSMF. In fibrotic connective tissue lesions without marked inflammation such as OSMF, the main route of collagen degradation is by phagocytosis and not by extracellular digestion. [10] In OSMF, the reduction of phagocytic activity is inversely dose dependent to levels of arecoline, safrole and nicotine in saliva. [11] Arecoline causes a suppression of T cell activity which in turn decreases the cell mediated immunity and thus results in decreased phagocytic activity of the cells. [12]

 > High Copper Content in Areca Nut and Fibrosis Top

The average daily copper intake of copper by adults from diet in developing countries is between 0.6 and 1.6 mg/ day. [13] An adult Indian chewing areca nut daily consumes over 5 mg of copper /day. [14] The copper released during chewing is brought in direct contact with oral mucosal keratinocytes for prolonged periods of time. Earlier studies have shown that it takes 40 min for raised salivary copper levels to return to its baseline value. [2]

The uptake of copper into the epithelial cells is a non energy, non enzyme dependent diffusion. The copper is either bound to protein metallothione or transferred across the basolateral membrane. [15] At cellular level, there is evidence to support the role of membrane bound copper transporting adenosine triphosphate (Cu-ATPase) in uptake of copper by the cells. [16] The mechanism of copper accumulation into the cells is explained by the presence of an extracellular tripeptide called as GHL tripeptide (glycy-L- histidyl-L- lysine) which is released within the lamina propria zone of areca nut chewers during initial inflammatory phase of OSMF. The first two residues of GHL molecule are involved in bonding with copper, whereas the side chain lysine may be involved in recognition of receptors that function in uptake of copper into the cells. [17]

Copper also causes upregulation of lysyl oxidase enzyme which plays a crucial role in cross linking of collagen and elastin molecules. Lysyl oxidase is a copper-dependent enzyme which is also an intrinsic protein of connective tissue. It is induced at detectable levels during fibrogenesis and fibroproliferative process. [18]

Copper may also bind to the protein product of p53 causing p53 aberrations in the oral keratinocytes. [2] In a study it was found that the concentration of copper in saliva, which can cause significant increase in collagen synthesis, was found to be 2-4 μg, whereas the peak effect was noted at 50 μg of copper chloride. [19] Studies done to evaluate serum and tissue copper levels in OSMF patients showed raised tissue copper levels in buccal mucosal biopsies of OSMF patients. The tissue copper levels measured by mass absorption spectrometry showed that the tissue copper levels in OSMF patients were 5.5 μg / gm compared to 4 μg/ gm in non areca nut chewers. Also the concentration gradient of copper was noted in lining mucosa with higher content of copper in epithelium compared to deeper connective tissues and muscle layers. Also raised copper was demonstrated in fibrotic side than non fibrotic side in unilateral OSMF patients' biopsies. Thus the site on which patient habitually kept the quid had increased copper levels. This, along with the length of time quid chewed, consistency of the quid, affects the uptake of copper by the epithelium. [2]

However the serum copper, ceruloplasmin, urinary and fecal copper levels of OSMF patients were within the lab reference ranges. Also no fibrosis was found elsewhere in the body suggesting the local effect of copper as the oral cavity is directly exposed to copper challenge. [20] Copper also affects specific growth characteristics of fibroblasts. The cell doubling time of OSMF fibroblast was reported to be 3.2 days as compared to 3.6 days for normal fibroblasts when they were cultured under influence of copper. [21]

 > Increased Expression of Fibrogenic Cytokines Top

It has been postulated that external stimuli such as areca nut may induce OSMF by increasing the levels of cytokines in lamina propria and also increasing the production of cytokines by the peripheral mononuclear cells. [22] The epidemiology of OSMF strongly suggests an individual susceptibility which could be cytokine based, especially as initial feature of OSMF is chronic inflammation accompanied by fibrosis. Also upregulation of proinflammatory cytokines ie IL-6 and IL-8 has been seen. It may be due to the T-cell activation, which occurs secondary to the chronic inflammation. Also an upregulation of certain fibrogenic cytokines such as TNF-α, TGF-β, platelet-derived growth factor, basic fibroblast growth factors is seen in OSMF. An under expression of antifibrotic cytokine interferon-gamma may also contribute to increased fibrosis. The above features are suggestive of an altered immune response in circulating monocytes along with an increase in number of local antigen presenting cells and lymphocytes in OSMF patients. This increases the genetic susceptibility of these patients and thus causes the penetration of arecoline and arecadine into the oral mucosa. [23]

Also TGF-α mediated actions cause altered collagen synthesis.

Increased collagen synthesis is by:

  • Activation of procollagen gene
  • Elevation of procollagen proteinase levels
  • Upregulation of lysyl oxidase activity

Decreased collagen degradation is by:

  • Activation of TIMPs (tissue inhibitor of matrix proteinases) gene. TIMPs gene inhibits activated collagenase which decreases the collagenase activity.
  • Activation of plasminogen activator inhibitor (PAI). PAI prevents conversion of plasminogen to plasmin, which is required for conversion of procollagenase to collagenase. [24]

 > Upregulation of Cox-2 Inflammatory Changes Top

It is known that OSMF is associated with inflammatory changes in at least some stage of the disease. Biopsies from buccal mucosa of OSMF patients have shown an increased expression of cyclooxygenase enzyme. Its production is controlled by the major inflammatory mediator prostaglandin. This correlates with the histology of the disease in which inflammatory cells are seen in early cases and they disappear as the disease advances. [25]

 > Stablization of Extracellular Matrix Top

Increased deposition of ECM takes place in OSMF as a result of disruption of equilibrium between matrix metalloproteinase's (MMP) and tissue inhibitors of matrix proteinases (TIMP). In response to arecoline, OSMF fibroblasts cause increased expression of TIMP-1 at the mRNA transcription level. Also there is a decrease in main gelatinolytic protein MMP-2 and MMP-9 secreted by buccal fibroblasts. [26] Also heparin sulfate proteoglycan, fibronectin and type 3 collagen and elastin appear in early and intermediate stage and completely replaced by type 1 collagen in advanced stages. [27] This pattern of expression of these molecules follows a similar pattern as seen in organization of granulation tissue. Thus OSMF can be said to be an altered phase of wound healing.

 > Collagen-Related Genes Top

OSMF is a disease of dysregulation in collagen metabolism, so it is important to identify the enzymes and molecules which may contribute to the genetic modulation of the disease. Different enzymes such as collagenase, lysyl oxidase along with cytokine TGF-β have been implicated in this context. The genes COL1A2, COL3A1, COL6A1, COL6A3 have been linked with the progression of the disease. [24] Also polymorphism of gene coding for TNF-α has been reported in OSMF which in turn inhibits collagen phagocytosis. [28] In another study, a possible relationship existed between the major histocompatibility complex class I chain related gene A (MICA) and OSMF. The study showed that the phenotype frequency of allele 6 of MICA in test subjects was significantly higher than that of controls.

 > Immunologic Factors Top

Many investigators suggest an autoimmune basis for this disease. It may be because of the presence of HLA A10 and DR3, DR7 antigens found in OSMF patients. [29],[30] Also increased autoantibodies directed toward the gastric parietal cells, thyroid gland , antinuclear antibodies, antismooth muscle antibodies has been seen in OSMF. [31] Humoral immunity may also play a role as increased circulating immune complexes and increased serum levels of IgG and IgA have been found in OSMF patients. [32] Serum-derived antibodies provide a further basis for an increase in mucosal permeability and accentuate the already existing pathologic condition. [33],[34] An important link between OSMF and decreased immune response may be the suggested viral origin of the disease (HSV, HPV). Viral lesions show similar immune derangements such as abnormal CD4/CD8 cell ratio as seen in OSMF. [35] Also viral antigen can elicit specific suppressor T-cell response. The resulting immunosuppression allows the spread of viral antigen and associated transformation of epithelium. A defect in target cell or viral cell lysis is seen by NK cells in OSMF. [36]

 > Nutritional Deficiencies Top

Several investigators have reported iron, vitamin, protein deficiencies in OSMF. [37] OSMF is basically a collagen disorder. [38] Hydroxyproline is an aminoacid found only in collagen and is incorporated in collagen in hydroxylated form (4 hydroxyl proline). This reaction requires iron and ascorbic acid. The decrease in iron levels may be due to utilization of iron in fibrosis. [39] Lack of iron causes improper vascular channel formation and concomitant decrease in vascularity. This makes perlocation of esters of arecoline easier. Also for normal epithelium maturation iron containing enzyme cytochrome oxidase is required. In iron deficiency, levels of this enzyme is low and consequent atrophy of epithelium results, which leads to burning sensation and ulcerations of oral cavity in areca chewers. This causes consumption of solid food unpalatable for the patient, leading to anemia. Thus it forms a vicious cycle. [40]

 > Chemical Carcinogenesis and OSMF Top

Lime which is a major component of betel quid preparations causes changes of oral environment of chewers from neutral to alkaline. Under the alkaline condition areca nut ingredients releases reactive oxygen species (ROS). [41] Also at pH> 9.5 areca phenols (tannins and catechins) undergo auto oxidation to release superoxide radicals and H 2 O 2. Also transition metals ions Cu 2+ , Fe 2+ , Fe 3+ promote ROS production by interacting with areca nut constituents. [ 42 ] These ROS are capable of inducing nucleotide modification by forming a compound called as 8-hydroxydeoxyguanosine. This compound leads to formation of mutated initiated cells during replication. It is also used as a biomarker to predict the attack by chemical carcinogens in the body. [ 43 ]

 > Incorporation of Copper in Areca Nut Top

Geographically, areca nut plantations are widely distributed in South east Asia, East Africa, India, Sri Lanka, Bangladesh, Myanmar, Thailand, Cambodia, Vietnam, Philippines, Taiwan. In India, it is grown in West Bengal, Assam, Tripura, Meghalaya, Mizoram, Nagaland, Manipur, North and South Kerala, Coastal Karnataka districts. Betel nut palm is ideally suited for ever wet climate with evenly distributed rainfall of 1500-5000 mm and even temperatures of 15.5- 38C. The best months for planting areca nut are during pre monsoon period of May-June with the onset of monsoon. The areca nut palm is prone to a number of diseases during different stages of its development. The warm, damp interval of monsoon showers is an ideal environment for diseases to occur. To prevent the diseases, growers spray 1% Bordeaux mixture in 10 L of water as a prophylactic spray just before the onset of monsoon. Some growers spray it twice / thrice depending on the intensity of rainfall. Bordeaux mixture is a fungicide which is prepared by adding milk of lime to a solution of copper sulfate until alkaline reaction is obtained. [44] Because of this, the areca palms are able to withstand the heavy rainfall. The spray gives a coating on the tender nut and prevents it from rotting and falling off. Thus post monsoon, the riped nuts are picked.

The composition of the tender nut includes alkaloids (arecoline), polyphenols, fat, crude fiber, protein, polysaccharides and water. [45] In this article, we emphasize that the incorporation of copper into the areca nut is through the Bordeaux mixture which is sprayed as a fungicide on areca plantations in regions with scheduled monsoons and of which copper sulfate is an important constituent. There is evidence to suggest that the metal matrix binding of copper in plants is associated with lectins and glycoproteins. [14] This copper incorporated in the nut and leaves is again absorbed by the plant as the leaves and nut shed off and get decomposed and absorbed within the soil.

The copper content of various constituents of quid are red areca (18.3ppm), white areca (14.9 ppm), betel leaf (18.5 ppm), gutkha (13.2 ppm), flavored areca (12.2 ppm), tobacco (6.3 ppm). The above data shows that betel leaf contains highest amount of copper. [46] The processed form of betel nut ie the freeze-dried products (panmasala, gutkha, mawa) contain higher concentration of copper as compared to raw form, this may be because of the copper which is added to it as a preservative.

Studies have also shown that spring and summer areca nut has differences in concentrations of majority of its elements except Mg, which exhibits consistency. Ca, Cl, Cu in summer areca nuts show low concentrations where as Br and Zn show higher concentrations. [47] It may be because Bordeaux mixture is not sprayed in regions of dry terrain as the crop is not likely to get diseased and damaged by the heavy rain fall.

Thus, it is emphasized that further research is required to validate the incorporation of copper into areca nut through Bordeaux mixture. Also the water level of the areca plantations should be assessed for the copper concentration to correlate the present notion of spraying of Bordeaux mixture and increased copper in areca plantations grown in the monsoon terrains.

 > References Top

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Chetan Hasmukh Mehta, Reema Narayan, Shruthi Acharya, Usha Yogendra Nayak
Journal of Drug Delivery Science and Technology. 2021; 66: 102911
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9 Efficacy of Oil Pulling in the Management of Oral Submucous Fibrosis: A Preliminary Study
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10 Does autofluorescence help detect recurrent squamous cell carcinoma? A prospective clinical study
Lara Schorn, Madiha Rana, Anna Madry, Ramin Ipaktchi, Henriette Möllmann, Nils Claudius Gellrich, Majeed Rana
Oral Surgery, Oral Medicine, Oral Pathology and Oral Radiology. 2020; 130(3): 258
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Yanwei Luo, Fengxia Liu, Jie Guo, Rong Gui
Scientific Reports. 2020; 10(1)
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12 Photobiomodulation therapy inhibits oral submucous fibrosis in mice
Min-Hsuan Chiang, Kun-Tsung Lee, Chia-Hsin Chen, Ker-Kong Chen, Yan-Hsiung Wang
Oral Diseases. 2020; 26(7): 1474
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13 Sex Hormones and Inflammation Role in Oral Cancer Progression: A Molecular and Biological Point of View
Maria Contaldo, Mariarosaria Boccellino, Giuseppa Zannini, Antonio Romano, Antonella Sciarra, Alessandra Sacco, Giuliana Settembre, Mario Coppola, Angelina Di Carlo, Luigi D’Angelo, Francesco Inchingolo, Antonia Feola, Marina Di Domenico
Journal of Oncology. 2020; 2020: 1
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14 Hypothesizing the therapeutic potential of mesenchymal stem cells in oral submucous fibrosis
Supriya Kheur, Avinash Sanap, Avinash Kharat, Archana A. Gupta, A. Thirumal Raj, Mohit Kheur, Ramesh Bhonde
Medical Hypotheses. 2020; 144: 110204
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Daisuke ITO, Hatsuhiko MAEDA
Journal of Japanese Society of Oral Medicine. 2020; 26(1): 1
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16 Çocuklarda Görülen Agiz Içi Premalign Lezyonlar
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Subhendu Bikas Saha, Purusottam Som, Debi Prassnna Ghosal
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Xiaojing Ye,Jing Zhang,Rui Lu,Gang Zhou
Medical Hypotheses. 2014;
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Yoithapprabhunath, T.R. and Maheswaran, T. and Dineshshankar, J. and Anusushanth, A. and Sindhuja, P. and Sitra, G.
Journal of Pharmacy and Bioallied Sciences. 2013; 5(SUPPL.1): S85-S88
23 Arecoline suppresses HaCaT cell proliferation through cell cycle regulatory molecules
Zhou, Z.-S. and Li, M. and Gao, F. and Peng, J.-Y. and Xiao, H.-B. and Dai, L.-X. and Lin, S.-R. and Zhang, R. and Jin, L.-Y.
Oncology Reports. 2013; 29(6): 2438-2444
24 Dietary copper: A novel predisposing factor for oral submucous fibrosis?
Arakeri, G. and Brennan, P.A.
Medical Hypotheses. 2013; 80(3): 241-243
25 Inflammation in the context of oral cancer
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