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Collagen  /certified fixed orthodontic courses by Indian dental academy Collagen /certified fixed orthodontic courses by Indian dental academy Presentation Transcript

  • INDIAN DENTAL ACADEMYLeader in Continuing Dental Education www.indiandentalacademy.com
  • Contents• Introduction• Structural features• Sequence of amino acids in chain• Basic events in synthesis• Some mediators that affect collagen synthesis• Degradation & remodelling• Disease associated with collagen alteration• Collagen metabolism & periodontal disease• Applied aspect of collagen• Conclusion• References
  • INTRODUCTION•Collagens are the most abundant proteins in the humanbody & they are found in species ranging from insects toman.•The word collagen is derived from Greek roots kolla(glue) and gene, and in French, the word collagenedesignates glue-producing constituents becausecollagenous tissues are used as the sources of glue &gelatin.
  • •It is the most abundant protein comprising of a largefamily of related but genetically distinct proteins. It isoften presumed to be most important in terms of toothsupport.•The collagen molecule is a rigid, rod-like structure thatresists stretching; the fibers made up of collagen have hightensile strength. Therefore, this protein is an importantstructural component in tissues such as PDL & tendon inwhich mechanical forces need to be transmitted withoutloss.
  • •Apart from their structural role, collagens can alsoinfluence cell shape, differentiation, & many othercellular activities, thus forming an important group ofmultifunctional connective tissue proteins thatparticipate in many biologic functions.•The collagen family consists of 30 different geneswhich produce 19 known types of collagen(Prockop & Kivirikko 1995). As a group of proteins, the collagens contain a number of characteristicfeatures that distinguish them from other matrixmolecules.
  • STRUCTURAL FEATURESAll collagens are composed of three polypeptide alphachains coiled around each other to form the typicalcollagen triple helix configuration.Common features include the presence of amino acidglycine in every third position, a high proportion of prolineresidues, and the presence of hydroxyproline &hydroxylysine
  • SEQUENCE OF AMINOACIDS IN COLLAGEN CHAINThe sequence consists of repeating tripeptides of glycine-X-Y where X & Y represent amino acids other than glycine.X is often proline & Y residue is often the aminoacidsderived from it (hydroxyproline). HYDROGEN BONDS
  • Collagens frequently are categorized as belonging to oneof several groups based on the structure of collagenmolecule, how the molecules are assembled, & their tissue,cellular & sub cellular distributions.Mesenchymal cells & their derivatives (fibroblasts,chondrocytes, osteoblasts, odontoblasts, & cementoblasts)are major producers of collagens. Many other cell types(epithelial, endothelial, muscle & Schwann cells) alsosynthesize collagens although on a more limited basis interms of amount & variety of collagen types
  • The collagen fibers have a transverse striation with achronic periodicity of 64nm which is caused byoverlapping arrangement of tropocollagen molecules.The molecular configuration confers to them a tensilestrength greater than that of steel.Therefore collagen imparts a unique combination offlexibility & strength to tissues where it lies.
  • BASIC STEPS IN COLLAGEN SYNTHESISThe collagen molecule is insoluble under physiologicalconditions It contains hydroxyproline & hydroxylysine, two aminoacids that are post-translationally modified from peptidylprolines & lysines. These modifications can occur only on nascent alpha chainsbecause the triple helical design is not accessible tomodification enzymes.The collagen molecule is first synthesized as a largeprecursor containing extra aminoacids at both N-terminal & C-terminal ends.
  • •Synthesis of these pro alpha chains, their assemblyinto procollagen & their conversion to collagen fibersinvolve several well coordinated biosynthetic reactionsoccurring in nucleus, cytoplasm & extra cellular space.STEPS 1. Nuclear events 2. Intracellular events 3. Extra cellular events
  • NUCLEAR EVENTS Gene expressionCollagen genes are large & range from 5 kb – 130 kbMore than 30 genes have been described for collagen type I to XIX.Fibril forming collagen genes contain 42 exons for major triple helicalregion, separated by introns 80 – 2000 nucleotides long.Most of these exons are composed of 54bp & start with an intact codonfor glycine.In type IX collagen, the sizes of exons range from 21 to 400 bpFor type IV & VI 34 exons of size 9bp.
  • Transcription of m RNA:•The first step involves the formation of transcriptioninitiation complex by RNA polymerase II.•This begins at an adenine base +1 location preceded bycytosine at -1•The consensus sequence for transcription initiation ispyridine (ANT).•After synthesis of about 30 nucleotides, the transcript ismodified at 5’ end by capping.
  • Capping:•It involves 5’-5’linkage of 7-methylguanine by theenzyme guanyl transferase.•Capping appears to be necessary for recognition ofmRNA by the nuclear transport to the cytoplasm, & italso renders the mRNAs resistant to nucleases.Polyadenylation:•Pre mRNA undergoes additional tailoring reactionsbefore it is converted into mature transferable form.•This pre mRNA is longer by 1000 bases at 3’end, this isremoved by endonuclease.
  • •After this endonuclease action mRNAs are rapidlypolyadenylated by the addition of about 200 adenines.Splicing:•It is a process by which intron sequences are removedfrom the pre-mRNA.•It involves two transesterification reaction in whichester group are exchanged & exon ends combinedtogether.
  • Intracellular eventsMessenger RNA directs the assembly of specificaminoacids into polypeptide chains on ribosomes of roughendoplasmic reticulum.These chains are 1-1/2 times longer than those ofcollagen molecules as they have N&C terminal extensionsthat are necessary for the assembly of triple helix molecule.As these chains are synthesized they are translocated inthe lumen of rough endoplasmic reticulum where post-translational modifications occur.
  • .Firstmodification being hydroxylation of proline & lysinewhich permits H+ bonding as triple helix is assembled. Thevitamin C dependant enzyme polyhydroxylase & lysylhydroxylase are required for this step.3 polypeptide chains then are assembled the triple helix.Proper alignment of the chains achieved by disulfidebonding at the C-terminal extension, & then the three chainstwist around themselves to “ zip up” the helix.The assembled helix then is transported to the golgicomplex,where glycosylation is completed by the addition of glucose tothe galactose residues.
  • Exocytosis : Secretory granules containing the procollagenmolecules are formed at the transface of the golgicomplex &are released subsequently by exocytosis at the cell surface.The formation & secretion of the collagen molecule takesapproximately 35-60 minutes.Extracellular eventsRemoval of C & N terminals by procollagen peptidases.Alignmant of molecules to form fibrilsThey aggregate each otherUndergo crosslinking which helps in further stabilization ofthe fibrils.
  • Mineralization of collagen: During the formation of collagen based calcified tissues, deposition of apatite crystals is catalyzed by specific atomic groups associated with the surface, holes & pores of collagen fibrils.
  • Although a direct role by collagen is excluded,regulation of this process is believed to be achievedby non collagenous proteins.In bone 70-80% of mineral is located within thecollagen fibril; the rest is located in the spacesbetween fibrils.Sharpey’s fibres seen in bone & cementum areeffectively mineralized.
  • Previous work(Selvig,1965) has suggested thatSharpey’s fibres represent an embedding of the PDLfibres by entrapment in the advancing mineral front.This well defined interface between mineralized & nonmineralized collagen in the PDL implies some form ofstrict control mechanism which retains the width(approximately 200µm in the case of human PDL) ofunmineralized fibres.Some authors suggested that alkaline phosphataseactivity could play a key role in collagen calcification invivo.
  • Regulation of collagen synthesis:• The quantity & proportion of collagens within each tissue need to be precisely regulated1. to maintain tissue integrity2. to control the amount of collagen produced3. to control the fiber architecture.• During development, inflammation & wound repair, the synthesis of collagen is influenced by various factors.
  • SOME MEDIATORS THAT AFFECT COLLAGEN SYNTHESISMediator Major source Collagen synthesisGROWTH FACTORSPDGF platelets, macrophages, increases smooth muscle cells, epitheliumTGF-β Platelets, macrophages. increasesFGF platelets, macrophages, matrix increasesIGF serum matrix increasesCYTOKINES/LYMPHOKINESIL-1αβ macrophages, most cells decreasesIFN-γ lymphocytes decreasedTNF-α monocytes,macrophages decreasedHORMONESGLUCOCORTICOIDS decreasedOTHERSPGE2 monocytes &macrophages decreased
  • •During initial stages of healing, after 1 day, type IIIcollagen is the major species produced, & type I collagensynthesis becomes prominent later.•The synthesis of collagen becomes maximal at 7-14 daysafter injury, & continues for weeks & months until tensilestrength of the wound is restored to normal levels.
  • CLASSIFICATION OF COLLAGENSCollagens are basically classified based on their chains,molecular distribution, length, tissue distribution &majorfunction.FIBRILLAR COLLAGENS [types I, II, III, V, & XI]Collagens I, II, III, V, & XI aggregate in a highlyorganized manner in the extra cellular compartment toform fibrils with a typical 64-nm banding pattern .
  • •In most connective tissues, type I collagen is the mostabundant collagen; type III collagen (reticular fibers) &type V collagen are usually present.•Type V collagen is found within fibrils of type I & IIIcollagen & is thought to regulate fibril diameter .•Type II collagen is abundant in cartilage;•type XI collagen is less abundant but heterotypic fibrilswith type II collagen.
  • BASEMENT MEMBRANE COLLAGEN [type IV]•Collagen IV is similar in size to type I collagen butdoes not assemble as fibers in the extracellularcompartment.•It contains frequent nonhelical sequences & aggregatesin a sheetlike, chicken wire configuration.•Type IV collagen is a major component of the basallamina & is a product of epithelial cells.
  • FACIT COLLAGENS [types IX, XII, and XIV]•Fibril associated collagen with interrupted helices[FACIT]•Consists of chains that have different lengths &contain a variety of noncollagenous domains.•They exhibit several interruptions in triple helix & arefound in various locations in different tissues
  • This collagen forms heterotypic fibrils with type IIcollagen in cartilage & vitreous humor.Type XII & XIV are believed to modulate interactionsbetween adjacent fibrilsMESHWORK- FORMING COLLAGENS [types VIII &X]Type VIII is associated with the basal laminae ofendothelial cells & smooth muscle cells & is present ionDescemet’s membrane of cornea. It imparts strength whileproviding an open porous meshwork.
  • Type X collagen is found almost exclusively in thehypertropic zone of the epiphyseal cartilage growth plate
  • ANCHORING-FIBIRL COLLAGEN [type VII]Collagen VII has unusually large non helical ends comprising twothird of the size of the molecule.The C-terminal ends associate to form the dimers that subsequentlyare assembled into the anchoring fibrils that extend from the basallamina into the underlying connective tissue.
  • MICROFIBRIL-FORMING COLLAGEN [type VI]Type VI collagen, which has large N & C terminalglobular domains associate in an end to end fashionforming beaded filaments.It is present in epimysium & most connective tissues.This collagen has binding properties for cells,proteoglycans, & type I collagen & may serve as a bridgebetween the cells & the matrix.
  • TRANSMEMBRANE COLLAGENS [type XIII & XVII]These collagens function in cell matrix adhesions.Type XVII is found in hemidesmosomes of basalepidermal cells & attaches the cells to the basal lamina. Type XIII is present in focal adhesion sites offibroblasts & at cell matrix interfaces in some epithelia,muscle, & nerves.It is also present in cell to cell adhesive specializationsof cardiac muscle, intercalated disks.
  • ENDOSTATIN FORMING COLLAGENS [types XV & XVIII]•Type XVIII is a component of basement membrane ofepithelial cells & endothelial cells, has multipleinterruptions in the central helical domain•It has a large unique C -terminal non-helical domainwhich can be cleaved by extra cellular proteases to formendostatin,a potent inhibitor of endothelial cell migration& angiogenesis.•Type XV type of collagen is present in papillaryepidermis as less potent angiogenic activity.
  • OTHERCOLLAGENS[typeXVI&XIX]Type XVI & XIX collagens have multipleinterruptions in their triple helical domain & an N-terminal globular domain.Their function & tissue distribution are incompletelycharacterized, but they have been shown to be associatedwith vascular, neural, muscular & certain epithelialbasement membranes.
  • TYPE I COLLAGEN MOLECULE In the α-chain of type I collagen, there are 338 Gly-X-Ytriplets repeated in a sequence, the additional 32 aminoacids flank the long triplet sequence at each end, which areknown as telopeptides. (Amino terminal & a carboxyterminal telopeptide.)Type I collagen molecule is a heterotrimer, that is two αchains are identical & third is distinct. Molecularcomposition can be written as (α1)2(α2). And type Icollagen composition is given as [α1 (I) 2[α2 (I)].
  • The three α-chains in each collagen molecule arewrapped around each other to form a long rigid triplehelical molecule & telopeptides remain free.Glycine is the smallest aminoacids & its replacementinhibits triple helix formationThe structure of collagen depends critically on thepresence of high amounts of proline & hydroxyproline;these aminoacids differ from other aminoacids as these areimino acids with a rigid cyclical structure, which isessential for stability.Type I collagen that lack hydroxyproline can form atriple helix at low temp, but triple helix falls apart at bodytemp.
  • COLLAGEN DEGRADATION & REMODELLINGCollagen degradation is a precisely controlled complexprocess.It is an essential concomitant of tissue development duringgrowth & of tissue maintenance in the adult.It also occurs during wound healing & inflammatoryresponses of tissuesSince collagen in connective tissue is in intimate contactwith glycoproteins, Proteoglycans & other components,these will influence susceptibility of collagen tissue todegradation extracellularly.
  • Intracellular degradation, considered as an importantmechanism for physiologic turnover & remodeling whereinphagocytosis of collagen fragments takes place bylysosomal enzymes [cathepsins]Problems in collagen destructionBulk of collagen is inaccessible within fibers & even theouter collagen molecules in these fibers are chemicallycross linked to each other & to those within fibers.The triple helical structure of collagen molecule cannotbe cleaved by proteases, trypsin, and pepsin except underextreme, essentially non physiological conditions.
  • DISEASES ASSOCIATED WITH COLLAGEN ALTERATIONSBecause most tissues contain a mixture of collagen types,any change in the structure, content, & proportion ofcollagen types can be expected to lead to functionalabnormalities of these tissues containing these collagensThree types of alterations can affect collagensA molecular defect in the processing enzymes - inheritedA defect in the structure of collagen genes – due to point mutationsMechanism affecting the expression of collagen genes due topathologies of acquired diseases – due to physiologic & environmentalfactors.
  • .Ex—1. Osteogenesis Imperfecta [Type I, II, III, IV]2. Ehler danlos syndrome [Type IV, VI, VII, VIII, & IX].3. ChondrodysplasiasEx—achondrogenesis, spondyloepiphyseal dysplasia, Stickler syndrome(type II &XI)4. Alport syndrome.(type IV)5. Dystrophic epidermolysis bullosa (type VII &XVII
  • COLLAGEN IN PERIODONTAL CONNECTIVE TISSUE:1)GINGIVA:• The various cell fibers of the gingival connective tissue provide a rigid structural framework in the gingiva.• These provide 60% of the total tissue protein• Ratio of type I collagen to type III is 7:1
  • •Type I is organized into denser fibrils, seen in deeperpart•Type III is localized mostly as thinner fibers &distributed in a reticular pattern, seen in superficialpart.•Type IV is synthesized by endothelial cells & theectodermal cells of the basement membrane of theoverlying epithelium
  • There are 11 types gingival fibers :1. Dentogingival2. Dento periosteal3. Alveologingival4. Cicrular5. Semicircular6. Transgingival7. Intergingival8. Transseptal9. Interpapillary10.Intercircular11.Periosteogingival
  • 2) PERIODONTAL LIGAMENT:•Major collagen types: type I & type III•Type III fibers when formed are of smaller diameter than typeI & appear to be more suited to withstanding deformation thanare type I fibers, thus it shows more elasticity.•Other collagens in less proportions are type IV & V
  • •One of the novel collagen components of the PDL is typeXII collagen, which is believed to be involved in the 3-dimensional organization of the extra cellular matrix.•This collagen is restricted to mature tissues & is notexpressed during development.The principle fibers of PDL:• Alveolar crest group• Horizontal group• Oblique group• Apical group• Interradicular group
  • Collagen fibers & tooth eruption:• It is known that collagen turn over is inversely proportional to the tensile strength & directly proportional to the remodeling activity.• The dual function of support & eruption of teeth appear to demand conflicting roles for PDL.• During eruption fibroblasts move from a basal position in an occlusal direction & PDL fibroblasts possess a system of microfilaments & microtubules which make their movement active process.
  • •Hence they move by means of collagenous attachment,pull the teeth with them as they migrate.•During hypo function, the collagen may be replaced byless aggregated forms of collagen, those that are newlyformed are also degrade into collagen fibrils & hence thinPDL in such cases.•The increased turnover of prefibrillar forms of collagen inassociation with a net loss of the extracellular fibrillarcollagen may also be an important factor in the mechanismof tooth eruption.
  • 3) CEMENTUM:•Composed of type I & type III – predominantlyseen•Type V in minute amount seen in Sharpey’sfibers.4) ALVEOLAR BONE:•Predominantly type I, expressed by osteoblasts•Type III also seen
  • COLLAGEN METABOLISM & PERIODONTAL DISEASESCIPD [chronic inflammatory periodontal disease] involvesthe net destruction of collagen in the extracellular matrix.Though etiology remains obscure, the unusual rapid rate ofturnover raises the possibility that the pathology is related todisturbances in the host synthesis/degradation pathway.Low level persistent bacterial infection could conceivablyresult in chronic inflammation leading to cytokine production& induction of MMPS by host cells.
  • Collagenase activity has been shown to be greater in thepresence of inflammatory periodontal disease.Christener in 1980 reported collagenase activity in humanperiodontal tissue only in periodontal ligaments from teeththat had suffered loss of attachment.Levels of tissue-derived collagenase were found to be higherin GCF of patients with CIPD, which were reduced aftertreatment
  • •MMPase activity was seen to increase at specific sites indiseased periodontium. [Heath &coworkers 1982]•Intracellular lysosomal digestion of collagen turnoverpathway could be abnormal during CIPD & this wassupported by findings of Morris & Harper [1987] whoreported decreased amounts of TIMP in CIPD
  • APPLIED ASPECTS OF COLLAGEN• During the course of periodontal disease morphological changes occur in the collagen fibers, the connective tissues of chronically inflamed gingival tissue contain types I,III,V,IV,VI• Type I synthesized in normal amounts• Type III less than normal
  • Reasons for this are:•Altered synthetic ability of fibroblasts•Toxic substanced inflamed tissues may alter allpopulations•Alteration in tissue serum levels; it has been found thatserum levels affect the synthesis rate of each type ofcollagen with type I, being formed faster than type III
  • •Along with collagen type I & III, a new collagen species,type I trimer, can be detected in inflamed gingiva.•This collagen is a homotrimer of the α1(I) chain, whichaccumulates in the absence of functional α2(I) chains incertain collagen molecular diseases, tumours.•Cementum may become altered due to its exposure tooral or pocket environment in which there is a loss ofcollagenous attachment & both its organic & inorganiccontent are changed.
  • • Early studies on the turnover of periodontal collagensfocused on measuring the hydroxyproline levels ingingival tissue extracts & GCF in an attempt to monitorperiodontal breakdown.( Hara & Takahashi 1975 )• The hydroxyproline content of GCF & serum has beenreduced significantly following periodontal surgery.
  • Gingival overgrowth:• Collagen content increases• Type I/III ratio becomes different with some loss of type I & elevated levels of type III collagen. ( Narayanan & Hassell 1985).• 2 mechanisms for accumulation:1. Decreased levels of matrix degrading enzymes in these lesions,2. Induction of collagen production.
  • Collagen induction occur•Directly by the action of drugs on collagen.•Indirectly, by decreasing the production of collagenase.(McCulloch & Knowles 1993)
  • AGE♦Increasing age results in coarser & denser gingivalconnective tissues.♦Qualitative & quantitative changes include an increasedrate of conversion of soluble to insoluble collagen, increasedmechanical strength, & increased denaturing temperature.♦Greater collagen content has been found in gingiva of olderanimals, despite lower rate of collagen synthesis decreasingwith age.
  • ALTERED COLLAGEN METABOLISM♦Increased collagen activity & decreased collagen synthesis is found inindividuals with diabetes & in chronic hyperglycemia.♦Gingival infllammation, bone destruction associated with localfactors are more severe in diabetics.♦In hyperglycemic state, numerous proteins & matrix moleculesundergo a nonenzymatic glycosylation, resulting in advanced glycationend products. [AGEs] The formation of AGEs can occur at normalglucose levels, but in hyperglycemic environment, AGEs formation isexcessive. AGE s formation cross links collagen , making it moresoluble, & less likely to be normally replaced or repaired ,as a result ofwhich poorly controlled diabetics is AGED & more susceptible tobreakdown.
  • GINGIVAL CHANGES♦Upto 70% of collagen is destroyed in the early lesion of gingivitis♦.In patients with periodontal pocket formation, the fibroblasts showcytotoxic alterations with decreased capacity for collagen production.♦P.gingivalis & Actinobacillus actinomycetemcomitans are the speciesof bacteriae producing collagenase.♦P. gingivalis possesses the proteolytic activity to degrade collageninto peptide components .The bacterial collagenase & the hostcollagenase, both contribute to collagen degradation.♦P. gingivalis produces gingipains [specific peptidases that cleaveproteins at peptide bond following arginine residues ]
  • ♦In LAP, predominant collagenase found in tissues & GCF is MMP-1 & increased TIMP-1 is present.♦Collagen fibers are non attached & run parallel to implant surface,owing to lack of cementum, an important difference between periimplant & periodontal tissues.♦Fibro-osseous system of implant retention suggests that thepresence of a dense collagenous tissue between implant & bone mayact as an osteogenic membrane♦Tetracycline impregnated collagen membrane delays degradationwhen 50 mg/ml of TCN solution concentration presented the highestdegree of MMP inhibition &TCN high concentration may affect thecollagen membrane integrity & enhance degradation. [J Periodontol2OO4]
  • ♦Expression of MMPS & TIMPS showed that in stage II gingivitis andstage III GINGIVITIS MMP-1, MMP-13, MMP-9 & TIMP-1 wereraised. [J Periodontol 2OO3]♦Cytokines linked to collagen breakdown during periodontal diseaseprogression from ELISA study showed that IL-Iβ stimulates boneresorption & decreased bone formation & IL-Iβ is considered as amarker of clinical severity of periodontitis [JPR 1996]
  • Changes in the regulation of collagen post-translationalmodification in transformed cells were studied in three establishedhuman sarcoma cell lines. The collagens synthesized by all but one of these and by all thecontrol human cell lines were almost exclusively of types Iand/orIII.The relative rate of collagen synthesis and the amounts of prolylhydroxylase activity and immunoreactive protein were markedly lowin all the transformed human cell lines. The other enzymes studied, lysyl hydroxylase, hydroxylysylgalactosyltransferase and galactosylhydroxylysylglucosyltransferase, never showed as large a decrease in activity asdid prolyl hydroxylase (Biochem J. 1981 Jun 15;196(3):683-92 )
  • ConclusionThey are synthesized in a series of biochemical events &theirsyntheses are highly regulated.Synthesis & turnover of collagens are prominent activitiesassociated with wound healing.Mechanism regulating collagen synthesis has a direct bearing onperiodontal structures in which collagens undergo dramatic changesduring periodontitis & drug induced gingival hyperplasia.Periodontal regeneration is also intertwined with eventsassociated with collagen production & degradation.
  • RefeRences• Oral histology – Tencates• Biology of the periodontal connective tissues – Bartold & Sampath Narayan• The periodontal ligament in health & disease – Berkovitz• Collagen & dental mattrices – J.P.Gage
  • Thank you