Collagen and collagen disorders

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Collagen is most abundant protein in mammals, 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. The collagen family consists of 28 members and these are classified by Roman numbers on the basis of their chronology of discovery.

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<ul><li> 1. Dr. Achi joshi Dept Of Periodontics SAIMS 1 </li></ul><p> 2. Introduction Structure Biosynthesis of collagen Types and functions of collagen Degradation and remodelling of collagen Biomedical applications Collagen in periodontal tissue Collagen disorders Conclusion 2 3. 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. 3 4. 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. 4 5. 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. 5 6. 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. 6 7. All collagens are composed of 3 polypeptide alpha chains coiled around each other to form the tripe helix configuration. The 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. 7 8. 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. 8 9. In the 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 chains are imino acids with a rigid cyclical structure. 9 10. 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. 10 11. 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 11 12. 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 12 13. 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. 13 14. 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. 14 15. 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 -ketoglutarate Ferrous ions Molecular oxygen Ascorbic acid (Vitamin C) 15 16. The enzyme galactosyl transferase catalyzes the addition of galactose to a hydroxylysyl residue . Glucosyl transferase catalyzes the further addition of glucose. 16 17. 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. 17 18. 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. 18 19. 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. 19 20. 20 21. 21 22. 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. 22 23. 23 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. 24. 24 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 25. 25 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 26. 26 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 calcication, Association with type II fibrils (?) 27. 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. 27 28. 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. 28 29. 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. 29 30. Collagen degradation The Collagenase Independent Intracellular Route The Collagenase Mediated Extracellular Route 30 31. Imbalance between activated MMPs and their endogenous inhibitors leads to pathologic breakdown of extracellular matrix during periodontitis. 31 32. 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. 32 33. 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. 33 34. 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. 34 35. Available in abundance and easily puried 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. 35 36. Formulated in a number of different forms. Biodegradability can be regulated by cross-linking. Easily modiable to produce materials as desired by utilizing its functional groups. Compatible with synthetic polymers. 36 37. High cost of pure type I collagen. Variability of isolated collagen (e.g. crosslink density, ber 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. 37 38. 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. 38 39. 39 40. 40 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 [1 (I) 2 (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. 41. 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. 41 42. 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. 42 43. 43 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 44. 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% 44 APICAL OBLIQUE INTER RADICULAR HORIZONTAL TRANSEPATAL ALVEOLAR CREST 45. 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 45 46. Majority of PDL collagen fibers are arranged in to Horizontal &amp; 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 46 47. 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 &amp; Oblique direction. 47 48. OVERLAPPING ARRANGEMENT of fibers as visible in Electron Microscope looks like the spokes of a cycle wheel. This is very crucial in withstanding Rotational &amp; Intrusive Forces. This overlapping arrangement helps in spreading the load uniformly and reduce the strain on PDL. 48 49. The terminal ends of the collagenous principal fibers are inserted in to bones to form Sharpeys 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. 49 50. 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. 50 51. S...</p>