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COLLAGEN AND COLLAGEN

DISORDERS Dr. Achi joshi

Dept Of Periodontics

SAIMS

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CONTENTS: Introduction

Structure

Biosynthesis of collagen

Types and functions of collagen

Degradation and remodelling of collagen

Biomedical applications

Collagen in periodontal tissue

Collagen disorders

Conclusion

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INTRODUCTION

Collagen is most abundant protein in mammals and accounts for 25-30% of

their protein content.

Collagen is the main fibrous component of skin, bone, tendon and cartilage.

Collagen comprises one- third of the total protein, accounts for three-

quarters of the dry weight of skin, and is the most prevalent component of

the extracellular matrix.

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The word collagen comes from the Greek word,

“kola,” meaning, “Glue producing”

French word, collagene designates glue-producing constraints because

collagenous tissue were used as source of glue and gelatin.

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When it is heated in water, it gradually breaks down to produce soluble

derived protein i.e. gelatin or animal glue.

Miller and Matukas discovered collagen in 1969, since then 26 new

collagen types have been found.

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The collagen molecule is a rigid rod like structure that resists stretching.

Therefore this protein is an important structural component in tissues such as the

periodontal ligament, muscles and tendons in which the mechanical forces need to

be transmitted.

Collagen can also influence cell shape, differentiation and many other cellular

activities. Thus, forming an important group of multifunctional connective tissue

protein that participates in many biological functions.

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STRUCTURE OF COLLAGEN All collagens are composed of 3 polypeptide alpha chains

coiled around each other to form the tripe helix configuration.

The α chains are left handed helices that wrap around each

other into a right handed rope like triple helical rod.

Each such helix is around 1.4 nanometers in diameter and

300 nanometers in length

The triple helix may be of a continuous stretch or it may be

interrupted by non collagenous elements.

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There are around 3 amino acids per turn.

The triple-helical sequences are comprised of Gly-X-Y

repeats, X and Y being frequently proline and 4-

hydroxy-proline, respectively.

Glycine occupies every third position in the repeating

amino acid sequence, it is essential for the triple

helical conformation because larger amino acids will

not fit in the center of the triple helix.

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In the α chain of type I collagen there are 338 Gly – X – Y triplets repeated

in a sequence and additional 32 amino acids flank the long triplet sequence

at each end. They are known as telopeptides. There is both an amino

terminal ( -NH2 ) and a carboxy terminal (-COOH ) telopeptide.

Proline and hydroxyproline in the α chains are imino acids with a rigid

cyclical structure.

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Stabilization of the triple helix is by-

the presence of glycine as every third residue,

a high content of proline and hydroxyproline,

inter-chain hydrogen bonds, and

electrostatic interactions involving lysine and aspartate.

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COLLAGEN BIOSYNTHESIS Collagen biosynthesis, starting with transcription of genes within nucleus to

aggregation of collagen heterotrimers into large fibrils is a complex multistep process.

The entire process of collagen biosynthesis-

Gene expression

Translational and post translational events or intracellular steps in collagen synthesis

Extracellular collagen biosynthetic events

Regulation of synthesis

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STEPS

There are more than 40 genes described for collagen types I to XXVIII.

Collagen is a structural protein and its synthesis is similar to synthesis of

any other protein molecule and involves process of transcription and

translation of genes.

From collagen genes mRNA for each collagen type is transcribed, it

undergoes many processing steps to produce a final code for that specific

collagen type. This step is called mRNA processing.

The initial RNA transcript is processed to mRNA and it gives rise to the

primary polypeptide chains in the ribosomes.

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The polypeptide chain formed initially is a helical molecule with two non-

helical extensions one at the NH2 and the other at the –COOH terminal end

(telopeptide)

The –NH2 terminal extension has a leader or signal sequence that directs

the entry of the molecule into the rough endoplasmic reticulum.

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The pre- pro-collagen molecule is converted to pro collagen molecule by

removal of signal peptide by signal peptidase and undergoes multiple steps

of post-translational modifications.

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HYDROXYLATION

Hydroxyproline and hydroxylysine are formed in the RER by the

hydroxylation of prolyl and lysyl residues. This is an essential step in

biosynthesis of collagen for it stabilises the molecules.

Requirements for hydroxylation are: Specific enzymes- prolyl hydroxylase and lysyl hydroxylase α-ketoglutarate Ferrous ions Molecular oxygen Ascorbic acid (Vitamin C)

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GLYCOSYLATION OF HYDROXYLYSINE The enzyme galactosyl transferase catalyzes the addition of galactose to a

hydroxylysyl residue .

Glucosyl transferase catalyzes the further addition of glucose.

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Formation of procollagen

Following hydroxylation and glycosylation, three polypeptide chains form a

triple helix .

Secretion of procollagen

Procollagen passes into the Golgi complex before its secretion into the

interstitial spaces.

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In the interstitial spaces,

Procollagen collagen.

Procollagen amino-peptidase and procollagen carboxylase catalyze the

removal of the two peptide chains that form the extension of the

procollagen molecule.

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Cross-linkage of fibrils to form fibres

There is oxidative deamination of specific lysyl or hydroxylysyl residues to form

aldehydes; the reaction is catalyzed by lysyl oxidase.

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TYPES OF COLLAGEN The collagen family consists of 28 members and these are classified by

Roman numbers on the basis of their chronology of discovery.

Variations are brought by

Differences in the assembly of basic polypeptide chains

Different lengths of the helix

Various interruptions in the helix and

Differences in the terminations of the helical domains.

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FUNCTIONS Type Function

I Provides tensile strength to connective tissue

II Provides tensile strength to connective tissue

III Forms structural framework of spleen, liver, lymph nodes, smooth muscle,

adipose tissue. Provides tensile strength to connective tissue

IV Forms meshwork of the lamina densa of the basal lamina to provide

support and filtration

V Provides tensile strength, associated with type I collagen, also with

placental ground substance.

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VI Bridging between cells and matrix (has binding properties

for cells, proteoglycan, a type I collagen)

VII Forms anchoring fibrils that fasten lamina densa to

underlying lamina reticularis

VIII Tissue support, porous meshwork, provide compressive

strength

IX Associates with type II collagen fibers

 

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X Calcium binding

 

XI Provides tensile strength, controlling lateral growth of type II fibrils

XII Associated with type I collagen fibers

 

XIII Cell matrix and cell adhesion

 

XIV Modulates fibril interactions

XV Proteolytic release of antiangiogenic factor

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XVI Unknown

XVII Cell to matrix attachment

 

XVIII Proteolytic release of antiangiogenic factor

 

XIX formation of hippocampal synapses

XXIV Regulation of type I fibrillogenesis, marker of osteoblast

differentiation and bone formation

XXVII cartilage calcification, Association with type II fibrils (?)

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DEGRADATION AND REMODELLING OF COLLAGEN

Extracellular matrix remodeling requires the degradation of its components. In

general, four types of proteolytic enzymes, capable of ECM degradation, exist:

Matrix metalloproteinases (MMPs)

Serine proteinases (e.g. plasmin)

Cysteine proteinases (e.g. cathepsin K) and

Aspartic proteinases.

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The MMPs are considered to be essential for the degradation .

The collagenases are responsible for the first degradation step of collagen,

in which the fibers are cleaved into the characteristic 1/4 and 3/4

fragments.

Gelatinases and cysteine proteases further degrade the collagen

fragments.

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Collagen degradation is an essential component of tissue development

during growth and of tissue maintenance in the adult.

Collagenases are widely distributed in the tissues and they bring about

collagen turnover, which is under physiological control, and can bring about

pathological destruction of connective tissue or provoke excessive new

collagen deposition and fibrosis.

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PATHWAYS OF COLLAGEN DEGRADATION

Collagen degradation

The Collagenase Independent Intracellular Route

The Collagenase Mediated Extracellular Route

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Imbalance between activated MMPs and their endogenous inhibitors leads

to pathologic breakdown of extracellular matrix during periodontitis.

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BIOMEDICAL APPLICATIONS

Collagen is regarded as one of the most useful biomaterials.

The excellent biocompatibility and safety due to its biological

characteristics, such as

biodegradability

biocompatibility

weak antigenicity.

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USES To repair tissues such as bone, tendon, ligament, skin, vascular and connective tissues.

Drug delivery applications: to develop scaffolds for delivery of genes, cell, growth

factors, anesthetics, analgesics, antibiotics etc.

For LDD in periodontal pockets

Tissue augmentation: For use in plastic surgery

To enhance blood coagulation and platelet activation

To enhance durability of allograft tissues.

In guided tissue regeneration.

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Can be used for the generation of bone substitutes, wound dressings,

nerve regeneration.

Artificial skin.

For use as a research tool to study diseases such as diabetes, aging and to

evaluate drugs.

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ADVANTAGES Available in abundance and easily purified from living organisms

(constitutes more than 30% of vertebrate tissues)

Non-antigenic.

Biodegradable and bio-reabsorbable.

Non-toxic and biocompatible.

Biological plastic due to high tensile strength and minimal expressibility.

Hemostatic — promotes blood coagulation.

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Formulated in a number of different forms.

Biodegradability can be regulated by cross-linking.

Easily modifiable to produce materials as desired by utilizing its functional

groups.

Compatible with synthetic polymers.

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DISADVANTAGES

High cost of pure type I collagen.

Variability of isolated collagen (e.g. crosslink density, fiber size, trace impurities,

etc.)

Hydrophilicity which leads to swelling and more rapid release.

Variability in enzymatic degradation rate as compared with hydrolytic degradation.

Complex handling properties.

Side effects, such as bovine spongeform encephalopathy (BSF) and mineralization.

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COLLAGEN IN PERIODONTAL TISSUES The collagen of periodontium is largely Type I , with lesser amounts of type

III , IV , VI and XII.

Collagen fibers of the periodontium ( particularly Type I ) provide the

structural requirements to withstand intrusive forces of mastication ( tooth

support ) and also to accommodate growing tooth in mammals.

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BONE COLLAGEN

Out of 22 to 25% of organic component 94 to 98% is mainly collagen type I.

It contains type I collagen predominantly with the molecular configuration of

[α1 (I) α2 (I)].

During its formation in the osteoblast the large procollagen precursor undergoes

important post translational modifications. Suitably located proline and lysine

residues are hydroxylated to hydroxyproline and hydroxylysine respectively.

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CEMENTAL COLLAGEN Predominant collagen present in cementum is type I

collagen (forms 90% of the organic matrix).

Other collagens associated with cementum include type III,

a less cross-linked collagen found in high concentrations

during development, repair, and regeneration of

mineralized tissues and type XII that binds to type I

collagen and to non-collagenous matrix proteins.

Collagens found in trace amount in cementum are types V,

VI and XIV.

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GINGIVAL COLLAGEN

Collagens are the most abundant biochemical constituents of gingival

connective tissue.

The collagen matrix of gingival CT is well organized into fiber bundles,

which constitute the gingival supra alveolar fiber apparatus.

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Based on their preferential orientation, architectural arrangement and sites

of insertion they are classified as-

1.Dentogingival

2.Dentoperiosteal

3.Alveologingival

4.Periosteogingiva

5.Circular and semicircular

6.Transgingival

7.Transseptal

8.Interpapillary

9.Intercircular

10.Intergingival

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PERIODONTAL FIBERS Periodontal ligament is composed of collagen fibers

bundles connecting cementum and alveolar bone

proper.

The vast majority of collagen fibrils in the periodontal

ligament are arranged in definite and distinct fiber

bundles and these are termed as principal fibers.

It contains type I and type III collagen, relative

proportion of type III to type I varies from 10-25%

APICAL

OBLIQUE INTER RADICULAR

HORIZONTAL

TRANSEPATAL

ALVEOLAR CREST

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Type III collagen fibers are smaller in diameter and appear to withstand deformation

better than type I. It also helps reduce fibril diameter with type I.

Type IV is found in the basement membranes and type V with cell surfaces(0.1-0.2%).

Major crosslink is of di-hydroxy-lysine while hydroxyl-lysine is a minor component

The presence of covalent cross-links between collagen molecules stabilizes the

ligament fibres and increases the tensile strength

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Majority of PDL collagen fibers are arranged in to

Horizontal & Oblique directed groups to adapt to

axial forces.

The complex 3D arrangement of fibers means that

some bundles would always be placed in Tension,

irrespective of the direction of an applied force. This

enables local areas of the PDL to resist compressive

forces

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FUNCTIONAL ADAPTATIONS OF COLLAGEN

Tooth support system is a multiphasic system comprising of

fibres , ground substances, blood vessels, fluids acting

together to resist mechanical forces.

Internal Orientation of collagen fibers influences the

mechanical properties of the tissue . Collagen fibers best

resist axially directed force as majority of PDL collagen fibers

are arranged in to Horizontal & Oblique direction.

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OVERLAPPING ARRANGEMENT of fibers as visible in Electron Microscope

looks like the spokes of a cycle wheel.

This is very crucial in withstanding Rotational & Intrusive Forces.

This overlapping arrangement helps in spreading the load uniformly and

reduce the strain on PDL.

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SHARPEY’S FIBER

The terminal ends of the collagenous principal

fibers are inserted in to bones to form Sharpey’s

Fibers.

These are enclosed within a sheath of collagen

Type III and it not only confers elasticity on the

fibers but it also maintains the elasticity of the

fibers when they are inserted in to the bone by

preventing their mineralization.

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COLLAGEN CRIMPING Collagenous tissues exhibit a quantifiable periodicity of structure of variable scale,

the waveform that describes this periodicity has been referred to as crimp.

In the polarizing microscope crimping can be seen by regular banding of dark lines

across the bundles.

Causes-

Sharp Zig-Zag arrangement of collagen fibers with quantifiable periodicity angular

deflection from axis

Microanatomical organization of collagenous sheets and bundles in sinusoidal wave

forms.

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Significance-

It is an early ,easily extensible , non linear region that causes the straightening

out of the crimp, this enables the ligament to absorb impact tensile loads

without extending collagen fibrils and without producing heat.

Fibroblast processes in the developing collagenous tissues play a role in

fabricating the crimped arrangement and consequently that crimping may be an

important feature in tooth eruption.

It also has been proposed that crimp some times can generate contractile forces

in collagen molecules.

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COLLAGEN DESTRUCTION IN INFLAMMATION

Gingivitis

Collagenolytic activity is increased in inflamed gingival tissue by the enzyme collagenase. Following

changes are seen in three different stages of gingivitis:

In initial lesion – perivascular loss of collagen can be seen.

In early lesion - increase in the amount of collagen destruction is seen, 70% of collagen is

destroyed around the cellular infiltrate.

This is necessary so that tissues can be pushed apart to accommodate the infiltrating cells and it is

considered to be a space creating process.

The main fiber groups affected appear to be circular and dentogingival fiber assemblies.

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In established lesion – collagen fibers are destroyed around the

infiltrate of intact and disrupted plasma cells, neutrophils, lymphocytes,

monocytes and mast cells.

Collagen loss continues in both lateral and apical directions as the

inflammatory cell infiltrate expands resulting in collagen depleted spaces

extending deeper into the tissues which are then available for leukocyte

infiltration.

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In periodontal pockets

Apical to the junctional epithelium, collagen fibers are destroyed and the area

becomes occupied by inflammatory cells and edema.

As the consequence of the lossof collagen,the apical cells of the junctional

epithelium proliferate along the root, extending finger like projections two or three

cells in thickness.

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COLLAGEN AS BIOMATERIAL IN PERIODONTICS

1. Drug delivery- For LDD in periodontal pockets

The key benefit of localised drug delivery over systemic therapy is that

high concentrations of drug can be maintained at the target site, while

avoiding risk of systemic toxicity and associated side-effects.

The drugs can be loaded into collagen membranes by hydrogen bonding,

covalent bonding or simple entrapment.

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PPAB is collagen fibril based formulation containing tetracycline hydrochloride (2 mg of tetracycline) in 25 mg of collagen fibrils.

Periocol®- TCSterile collagen Fibres with Tetracycline Hydrochloride for periodontal infections.

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2. Tissue augmentation- recession coverage

Collagen membranes are used as an alternative to connective tissue grafts

in mucogingival surgeries.

It shows similar histologic and clinical outcomes, achieving complete root

coverage when compared with connective tissue grafts.

It gets completely incorporated in the adjacent host connective tissues

without any signs of inflammation.

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3. Bone substitute- as bone grafts in intra-bony defects

Collagen has been used as implantable carriers for bone inducing proteins

Collagen itself is used as bone substitutes due to its osteo-inductive

activity.

Demineralized bone collagen is used as a bone graft material for the

treatment of acquired and congenital bone defects either by itself or in

combination with hydroxyapatite crystals.

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Osseograft/DMBM is one such de-mineralized bone derived Type-I collagen for bone void filling applications.

Dembone is Demineralized Freeze-dried Cortical Bone Powder, prepared from cortical bone harvested from carefully screened human donors, demineralized in HCl acid, freeze dried and triple sterilized before vacuum packing.

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SyboGraf™Sterile Synthetic Nanocrystalline Hydroxyapatite Bone Graft.particle size ranging from 200-300 and 600-700 microns.

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4. In guided tissue regeneration- GTR membranes

Guided tissue regeneration (GTR) is a procedure that attempts to reconstitute the lost

tissues and is based on the concept of selective repopulation.

The first report of a human tooth treated by guided tissue regeneration was by Nyman

et al in 1982, with the term GTR coined by Gottlow et al in 1986.

To exclude the fast-growing cells of the gingival epithelium from migrating to the

wound, GTR procedures use barrier devices that are placed between the periodontal

flap and the osseous defect to maintain a space for repopulation of the defect with

cells having regenerative potential.

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Healiguide thin sheet made of high purity Type-I collagen

derived from selected animal tissues. Periocol® / Helisorb®-GTRType 1 collagen membrane of fish origin for GTR applications

Cologuide

5. Hemostat

During the healthy process of blood clotting, platelets become activated by

thrombin and aggregate at the site of injury.

Stimulated by the protein fibrinogen, the platelets then clump by binding to the

collagen that becomes exposed following rupture of the endothelial lining of blood

vessels.

Collagen is therefore a natural haemostat and a wide variety of collagen-based

products are used in surgery and dentistry to control excessive bleeding or

haemorrhage. 64

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Absorbable sterile fibrillar collagen wound filler, constituted using high purity type-1 reconstituted collagen 

•Hemostatic agent•Control bleeding and stabilizes blood clots•Protects wound bed

GelSpon®

Sterile Absorbable Haemostatic Gelatin Sponges

 

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COLLAGEN DISORDERS

Collagen diseases may be genetic, auto-immune or miscellaneous like

defects due to nutritional deficiencies, drug induced defects etc. An inborn

error of metabolism involving abnormal structure or metabolism of collagen

results in collagen disorders. All these affect the biosynthesis, assembly,

post-translational modification, secretion, or other processes involved in

normal collagen production.

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GENETIC OR HERITABLE COLLAGEN DISORDERS

Heritable collagen disorders are caused by mutations in the genes coding

for collagen α chain.

The mutations affect the extracellular matrix by decreasing the amount of

secreted collagen, impairing molecular and supra-molecular assembly

through the secretion of a mutant collagen, or by inducing endoplasmic

reticulum stress and the unfolded protein response.

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OSTEOGENESIS IMPERFECTA The disease is characterized by-

extremely fragile bones

reduced bone mass

blue sclera,

hearing loss and

scoliosis.

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This is due to mutations in one of the two genes, COL1A1 and COL1A2,

which encode the two chains of type I collagen, the major protein of bone.

The most common mutations of this disease is due to substitution of

glycine with a bigger amino acid.

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EHLERS-DANLOS SYNDROME

Heterogeneous group of heritable disorders of connective tissue characterized by –

articular hypermobility

skin hyperextensibility, and

tissue fragility affecting skin, ligaments, joints, blood vessels, and internal organs.

Cause- mutations in the COL5A1 and COL5A2 genes encoding the α1 and α2

chains of type V are defined.

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ORAL MANIFESTATIONS

Gorlin sign

Early onset generalized periodontitis resulting in the premature loss of

deciduous and permanent teeth.

The gingiva is fragile and hemorrhage may be difficult to control during surgical

procedures.

Absence of the inferior labial and lingual frenula has been reported in EDS II,

EDS III and suggested to be a highly specific and sensitive marker for these

disorders.

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ALPORT SYNDROME

Alport syndrome is a progressive hereditary nephritis with Extra-

renal complications, like sensory-neural hearing loss and ocular

abnormalities.

Caused by deletion mutations in COL4A5 and COL4A6 genes or

COL4A3 and COL4A4 genes encoding the α3 (IV) and α4 (IV) chains.

X-linked

This syndrome affects some of the basal membranes and is

characterized by renal failure, loss of hearing and lens

abnormalities.

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EPIDERMOLYSIS BULLOSA Epidermolysis bullosa (EB) is a clinically and genetically heterogeneous group of

inherited disorders that are characterized by blistering of the skin and certain other

tissues.

Caused by

mutations in COL7A1, affecting the structure of type VII collagen.

Type VII collagen forms delicate fibrils that anchor the basal lamina to collagen

fibrils in the dermis.

These anchoring fibrils are reduced in this form of the disease, causing friction

and blistering.

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CHONDRODYSPLASIAS

A rare, inherited disorders of skeletal development and linear growth.

Involve disturbances of the cartilage components of the growing skeleton,

it is Mutations of the gene for type II collagen, COL2A1, produce a broad

spectrum of clinical phenotypes that fall under the general designation,

spondyloepiphyseal dysplasia (SED).

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KNOBLOCH SYNDROME

Knobloch syndrome is an autosomal recessive disorder

characterized by high myopia, vitreo-retinal

degeneration, occipital bone damage, and congenital

encephalocele.

pathological mutations in the COL18A1 gene at 21q22.3

have been identified.

These mutations cause the loss of one or all collagen

COL18A1 isoforms or endostatin.

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BETHLEM MYOPATHY

Bethlem myopathy is an autosomal

dominant inherited relatively mild disease

that is characterized by muscle weakness

and distal joint contractures.

Type VII collagen plays a role in

connecting cells and extracellular matrix

and that mutations in genes encoding

collagen VII result in Bethlem myopathy.

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STICKLER SYNDROME

It is a unique autosomal dominant

syndrome of premature osteoarthritis,

retinal degeneration, hearing loss and

orofacial abnormalities

caused by mutations in the COL2A1,

COL11A1 and COL11A2 procollagen

genes of type 2 and 1 collagen.

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SCHMID METAPHYSEAL CHONDRODYSPLASIA

This autosomal dominant disorder

usually presents after the age of

2–3 years with mild short stature,

bowing of the lower extremities,

and a waddling gait.

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OSTEOLATHYRISMOsteolathyrism is a collagen cross-linking deficiency caused by

dietary over-reliance on the seeds of Lathyrus sativus (kesari dal)

in some parts of India.

Osteolathyrogenic compounds like Beta-aminopropionitrile (BAPN)

and Beta-oxalyl aminoalanine [BOAA] found in Kesari dhal inhibit

enzyme lysyl oxidase required for the formation of cross links in

the triple helices

EFFECT

weakness and fragility of skin, bones, and blood vessels

Paralysis of the lower extremities associated with neurolathyrism

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AUTO IMMUNE DISORDERS

Collagen diseases share similarities with autoimmune diseases, because

autoantibodies specific to each collagen disease are produced.

Multiple organs may be affected.

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SYSTEMIC LUPUS ERYTHEMATOSUS

Lupus erythematosus is a multifactorial

autoimmune collagen vascular or

connective tissue disease, which may affect

the oral mucosa in either its cutaneous and

systemic forms with varied prevalence

Oral lesions include ulceration, pain,

erythema and hyperkeratosis. Other oral

complaints are xerostomia, stomatodynia,

candidiasis, periodontal disease and

dysgeusia.

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ORAL SUB MUCOUS FIBROSIS

This disease is considered to be a consequence of

disturbances in the homeostatic equilibrium between

synthesis and degradation of extracellular matrix,

wherein collagen forms a major component, thus can

be recognized as a collagen-metabolic disorder.

It is characterized by a juxta epithelial inflammatory

reaction followed by fibroelastic change in the lamina

propria and associated epithelial atrophy.

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MISCELLANEOUS

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SCURVY

Key function of ascorbic acid is its involvement in the synthesis of collagen fibers

from proline via hydroxyproline.

Other metabolic reactions for which vitamin C is required are the hydroxylation of

lysine into hydroxylysine in collagen.

In individuals who suffer from a deficiency of this vitamin, the α-chains of the

tropocollagen molecules are unable to form stable helices and the tropocollagen

molecules are incapable of aggregating into fibrils.

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Avitaminosis C is associated with the failure

of wound healing or the rupture of

capillaries due to intrinsic intercellular

weakness with lack of connective tissue

support of the capillary walls.

Oral manifestations –

Fetid odor and loosened teeth,

gingivae are boggy, ulcerated and bleed

easily

interdental and marginal gingiva become

bright red, smooth, swollen and shiny.

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METABOLIC DISORDER- DIABETES MELLITUS

In the hyperglycemic state, numerous proteins and matrix molecules

undergo a non‑enzymatic glycosylation, resulting in accumulated

glycation end products (AGEs).

Collagen is cross‑linked by AGE formation, making it less soluble and less

likely to be normally repaired or replaced.

As a result, collagen in the tissues of patients with poorly controlled

diabetes is aged and more susceptible to breakdown i.e., less resistant to

destruction by periodontal infections.

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GINGIVAL ENLARGEMENTS

1. Hereditary gingival fibromatosis

both dominant autosomal inheritance and recessive autosomal inheritance

It is a gradually progressive benign enlargement that affects the marginal,

attached, and interdental gingiva.

Histopathologically, it implies an increase in both extracellular matrix and

cell numbers.

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2. drug induced enlargement

A. phenytoin

Fibroblasts become sensitive to phenytoin, and this results in subsequent

increased production of collagen.

The enzyme collagenase secreted by phenytoin-sensitive fibroblasts is

relatively inactive to degrade collagen.

An imbalance in production and degradation results in the over

accumulation of collagen and hence in an increase in the bulk of

connective tissue.

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B. Calcium channel blockers

After an interaction between nifedipine and gingival fibroblasts,

overproduction of collagen and extracellular ground substance occurs and

leads to an increase in the size of the gingiva.

C. Cyclosporin induced

It was found that CsA could react with a phenotypically distinct

subpopulation of gingival fibroblasts to enhance protein synthesis.

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CONCLUSION

Collagens have ubiquitous distribution throughout the animal kingdom. Collagens

serve important mechanical functions within the body, particularly in connective

tissues and also exert important functions in the cellular microenvironment.

It is an important constituent of periodontium therefore knowledge of the structure,

biosynthesis and interactions of collagen with other components, its regulation and

degradation mechanisms and changes it undergoes with age and diseased state is

essential, for the understanding of the functioning of the periodontium.