Good AFTERNOON

Journal discussion

Molecular pathogenesis of oral submucous fibrosis –A collagen metabolic disorder (review article)

P. Rajalalitha, S. ValiJ Oral Pathol Med (2005) 34: 321–8

By: Dr. Madhusudhan reddy

II year PG

VDC

INTRODUCTION • Pindborg defined Oral submucous fibrosis as • “an insiduous chronic disease effecting any part of

the oral cavity and sometimes pharynx. Although ocassionally preceded by and/or associated with vesicle formation,, it is always associated with juxtraepithelial inflammatory reaction followed by fibroelastic changes in the lamina propria, with epithelial atrophy leading to stiffness of the oral mucosa causing trismus and difficulty in eating”

• Precancerous condition strongly associated with the use of areca nut and pan masala.

• First reported in 1952 by Schwatrz.• Its precancerous nature – reported by Paymaster

in 1956• Causes – multifactorial.

1) Areca nut chewing

2) Ingestion of chilies

3) Genetic and immunologic process

4) Nutritional deficiencies• Chewing betel quid (areca nut, tobacco, slaked

lime or other spices) is most important risk factors

• Predominantly seen in India, Bangladesh, Sri lanka, Pakistan, Taiwan, Southern China etc

• According 1996 world estimates 2.5 million people were effected with OSMF

• In Indian subcontinent 5 (0.5%) million (2002) • Malignant transformation rate of OSMF was

7.6% over 17 years period.

• Components of betel quid contains of alkaloids like

1) Alkaloids (arecoline, arecaidine, guyacoline, guacine)

2) Flavonoids (tannins, catechins)• These alkaloids directly influence on collagen

metabolism by

1) Increased secretion of collagen

2) Decreased degradation of collagen

• Collagen – major structural component of connective tissue.

• Synthesis of collagen is influenced by

1) Growth factors (TGF-β)

2) Hormones

3) Cytokines and Lymphokines

Initial events of the disease• Most areas betel quid – areca nut, slaked lime, catechu,

several condiments wrapped in the betel leaf.• Reasons for chewing betel quid are

Euphoria

Increased salivation

Satisfies hunger

Relieves tooth pain• These alkaloids undergo nitrosation and give rise to N-

nitrosamines, which might have a cytotoxic effect on cells. • Arecoline - promote collagen synthesis

• BQ is placed in the buccal vestibule for about 15 min to an hour and repeated five to six times a day.

• Constant contact between the mixture and oral mucosa.

• Alkaloids and flavonoids - chemical irritants. • Coarse fibers of BQ also causes mechanical

irritation leading to micro trauma. • Constant chemical and mechanical irritation leads

to juxtraepithelial inflammatory cell infiltrate.

• Molecular events in this review are discussed under two sections

1) Collagen production pathway

2) Collagen degradation pathway

Collagen production pathway

• Three main events in in collagen production • 1) Activation of procollagen genes by TGFβ• 2) Elevation of procollagen proteinases levels

(a) Procollagen C-proteinase (PCP)/

bone morphogenetic protein1 (BMP1)

(b) Procollagen N-proteinase (PNP)• 3) Up-regulation of lysyl oxidase (LOX) activity

C-TELOPEPTIDE

N- TELOPEPTIDE

• Collagen – structural element in connective tissue. •27 types of collagen - 7 broad classes• Fibrillar collagen – type I, III, VI, VII• Genes – COL1A2, COL3A1, COL6A1, COL6A3, COL7A1.

TGF-β

PNP Procollagen gene activation

BMP 1/PCP

Increased procollagen Pro LOX LOX

Increased collagen (soluble form)

Increased LOX

Increased collagen (insoluble form)

Increased collagen production

Flavonoids in areca nut

Increased copper in areca nut

Collagen degradation pathway

• There are two main events modulated by TGF-β, which decreases the collagen degradation

(i) Activation of tissue inhibitor of matrix metalloproteinase gene (TIMPs);

(ii) Activation of plasminogen activator inhibitor (PAI) gene

TGF-β

Activation of TIMP gene Activation of PAI gene

Increase TIMPsIncrease PAI

Inhibits activated collagenase

PlasminPlasminogen

Procollagenase Collagenase

Decrease in collagenase activity

Decrease in collagen degradation

Flavonoids in areca nut

conclusion• This review – described as collagen-metabolic disorder. • Increased collagen production • Decreased collagen degradation • Autoregulatory process of TGF-β – main trigger for OSMF • Understanding of the molecular events - better therapeutic

intervention of the disease.

Betel quid chewing habit

Chronic inflammatory process

TGF-β

Anti-inflammatory immuno-modulatory drugs

Anti-TGF-β

Collagen production

PNP PCP

LOX

Collagen degradation

TIMP Plasminogen activator system

Collagenase

Copper chelators

Anti LOX drug

Collagenase activators

• Anti-inflammatory immuno-modulatory drugs – colchicine, steroids.

• Anti-TGF-β – developmental form• Anti LOX drug, Copper chelators – D-Pencillamine.• Presently hyaluronidase (that breaks down the

components of connective tissue) intralesional injection along with steroid has been used for OSF therapy.

• Interferon-γ, an anti fibrotic cytokine has also been used.

• Probably a combinational therapy of the above mentioned drugs might be useful in the therapy