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Extracellular Matrix


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Extracellular matrix in health and disease

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Extracellular Matrix

  1. 1. 19.03.16 Saradbrata Mishra 119.03.16 Saradbrata Mishra Moderater Dr. Geetashree Mishra EXTRACELLULAR MATRIX IN HEALTH AND DISEASE Presented By Saradbrata Mishra
  2. 2. 19.03.16 Saradbrata Mishra 219.03.16 Saradbrata Mishra Discussion • Definition • Functions of ECM • Forms of ECM • Components of ECM • Abnormalities in ECM in different diseased states • Future therapeutic approaches by targetting ECM
  3. 3. 19.03.16 Saradbrata Mishra 319.03.16 Saradbrata Mishra DEFINITION • Extracellular matrix (ECM) is a network of interstitial proteins that constitutes a significant proportion of any tissue.
  4. 4. 19.03.16 Saradbrata Mishra 419.03.16 Saradbrata Mishra FUNCTIONS OF ECM In addition to space filler other functions are • Mechanical support- For cell anchorage and cell migration, and maintenance of cell polarity. • Control of cell proliferation- By acting as a depot of latent growth factors, binding and displaying growth factors, and signalling through cellular receptors. • Scaffolding for tissue renewal- Integrity of ECM is critical for the organized regeneration of tissues. So ECM disruption results in defective tissue regeneration and repair (eg. Cirrhosis of Liver). • Establishment of tissue microenvironments- Basement membrane acts as boundary between epithelium and connective tissue, and is also functional, eg in kidney BM forms part of the filtration apparatus. • Cellular interaction- For maintaining normal tissue architecture.
  5. 5. 19.03.16 Saradbrata Mishra 519.03.16 Saradbrata Mishra TWO BASIC STRUCTURAL FORMS OF ECM 1) Interstitial Matrix- • Present in the spaces between cells in the connective tissue, and between the parenchymal epithelium and underlying vascular and smooth muscle structures. • It is synthesized by mesenchymal cells (eg-fibroblast). • Forms a three dimensional amorphous gel structure. • Its major constituents are fibrillar & non fibrillar collagen, fibronectin, elastin, proteoglycan, hyaluronate and others. 2) Basement Membrane- • The interstitial matrix becomes highly organized around epithelial cells, endothelial cells & smooth muscle cells, and forms the specialized BM. • Synthesized by contribution of both underlying mesenchyme and overlying epithelium. • It is a porous structure forming a flat lamellar "chicken wire" mesh. • Its major constiuents are 1. Collagen IV 2. Laminin 12 3. Entactin/Nidogen 2 isoforms 4.Sulfated proteoglycans such as Perlecan and Agrin
  6. 6. 19.03.16 Saradbrata Mishra 619.03.16 Saradbrata Mishra COMPONENTS OF ECM Components of ECM are chatagorised into 3 groups of proteins; 1) Fibrous structural proteins- Collagens, Elastins & Fibrillin. Confer tensile strength and recoil. 2) Water-hydrated gels- Proteogylcans & Hyaluronan. Permit compressive resistance and lubrication. 3) Adhesive glycoproteins & receptor- Fibronectin, Laminin & Integrin Connect ECM elements to one another and to cells. 4) Water - 65%
  7. 7. 19.03.16 Saradbrata Mishra 719.03.16 Saradbrata Mishra
  8. 8. 19.03.16 Saradbrata Mishra 819.03.16 Saradbrata Mishra • The most abundant protein in the body, making 25%-35% of all the whole-body proteins. • About 30 collagens type have been identified, some are unique to specific cells and tissues. • Collagen contributes to the stability of tissues and organs. • It maintains their structural integrity. • It has great tensile strength. • Plays an important role in cell differentiation, polarity, movement. • Plays an important role in tissue and organ development. • Principal producers of collagen fibers are fibroblasts; epithelial and smooth muscle cells also secrete their own type-IV collagen. (1) COLLAGENS
  9. 9. 19.03.16 Saradbrata Mishra 919.03.16 Saradbrata Mishra COLLAGEN BIOSYNTHETIC PATHWAY
  10. 10. 19.03.16 Saradbrata Mishra 1019.03.16 Saradbrata Mishra INTRACELLULAR • mRNA attach to the rER, and protocollagen or precollagen-chains are deposited in the cisternae; every 3rd amino acid is glycine. • Proline and lysine residues within the chains are then hydroxylated in the ER to form hydroxyproline and hydroxylysine. • Core sugars (galactose and glucose) attach to the hydroxylysine residues in the ER. • Each chain is synthesized with an extra length of peptides known as registration peptides, which ensure that the appropriate chains assemble in their correct position in the resulting triple helical molecule called procollagen. • Glycosylation may occur in the Golgi complex and procollagen is released into the extracellular space by exocytosis.
  11. 11. 19.03.16 Saradbrata Mishra 1119.03.16 Saradbrata Mishra EXTRACELLULAR • In the extracellular space, the enzyme procollagen peptidase cleaves the registration peptides from procollagen, converting it to tropocollagen. • Catalyzed by lysyl oxidase(dependent on vitamin C), these become aligned in staggered fashion to form collagen fibers, possibly under the control of adjacent fiber-producing cells. • The turnover of collagen is slowest in tendons, fastest in loose connective tissue. Macrophages and neutrophils break down old collagen, and replaced by fibroblasts. • As humans age, extracellular collagen becomes increasingly cross- linked, & turn-over slows down in connective tissue.
  12. 12. 19.03.16 Saradbrata Mishra 1219.03.16 Saradbrata Mishra Contd.... • Prepro collagen → Procollagen → Tropocollagen → Fibrillar collagen. • Collagens are composed of three separate polypeptide chains, braided into a tripple helix structure. • There are 3 helical α chains. They may be identical in some type of collagens (Homotrimer) or different to each other in other types of collagens (Heterotrimer) Collagen polypeptide structure: - G – X – A – G – A – A – G – Y – A – G – A – A – G – X – A – G – A – – A – G – X – A – G – A – A – G – Y – A – G – A – A – G – X – A – G – G - glycine, X - proline or hydroxyproline, Y – lysin or hydroxylysine, A – amino acid • Due to rod like fibril stacking & lateral crosslinking, fibrillar collagens have marked tensile strength but do not have much elasticity.
  13. 13. 19.03.16 Saradbrata Mishra 1319.03.16 Saradbrata Mishra
  14. 14. 19.03.16 Saradbrata Mishra 1419.03.16 Saradbrata Mishra
  15. 15. 19.03.16 Saradbrata Mishra 1519.03.16 Saradbrata Mishra Diversity of Collagens
  16. 16. 19.03.16 Saradbrata Mishra 1619.03.16 Saradbrata Mishra (2) ELASTIN • Elastin is a major protein component of tissues that require elasticity such as arteries, lungs, cardiac valves, uterus, bladder, skin and elastic ligaments and cartilage. • Polypeptide chains are cross-linked together to form rubberlike, elastic fibers. Each elastin molecule uncoils when the fiber is stretched and recoils spontaneously as soon as the force is relaxed. • 90% of all the amino acid residues of elastin are nonpolar (characterized by a high index of hydrophobicity). • Elastic fibres consist of a central core made of elastin, surrounded by a peripheral network of microfibrils. • Over time, tropoelastin accumulates within the bed of microfibrils.
  17. 17. 19.03.16 Saradbrata Mishra 1719.03.16 Saradbrata Mishra Structure •Elastin is more massively crosslinked than collagen and also have large hydrophobic segments (unlike collagen) that forms globular configuration at rest. •As stretch is exerted the hydrophobic domains are pulled open, but the cross-link keep the tissue intact. •Release of stretch tension allows the hydrophobic domains of the proteins to refold. •Thus elastin has more elasticity and less tensile strength than that of collagen.
  18. 18. 19.03.16 Saradbrata Mishra 1819.03.16 Saradbrata Mishra (3) FIBRILLIN • Large glycoprotein secreted by EC fibroblast. • Found commonly in zonular fibres of the lens, periosteum, arterial wall. • In the elastic fibre the peripheral microfibrillar network that surrounds the core consists largely of fibrillin. • Types of fibrilin- 1.Fibrilin 1:- Major component of microfibril. 2.Fibrilin 2:- Have a role in early elastogenesis. 3.Fibrilin 3:- Mainly located in the brain. 4.Fibrilin 4:- Structure is similar to fibrilin 2.
  19. 19. 19.03.16 Saradbrata Mishra 1919.03.16 Saradbrata Mishra BIOSYNTHETIC PATHWAY OF ELASTIC FIBRE
  20. 20. 19.03.16 Saradbrata Mishra 2019.03.16 Saradbrata Mishra (4) PROTEOGLYCAN & HYALURONAN • Proteoglycans are composed of a core protein to which glycosaminolycans (GAGs) are attached. GAGs consist of repeating disaccharide subunits. • The core proteins are attached to long haluronic acid polymer.
  21. 21. 19.03.16 Saradbrata Mishra 2119.03.16 Saradbrata Mishra Contd.... • The highly negatively charged sulfated sugars on the proteoglycan "bristles" recruit sodium and water to generate a viscous but compressible matrix. • They have diverse role in regulating connective tissue structure and permeability (ie regulates movement of molecules through matrix). • They also serve as reservoir of growth factors (eg FGF & HGF), they act as modulators of cell growth and differentiation. • In joint cartilage they also provide layer of lubrication between bony surfaces. • Some are integral part of cell membrane & have roles in cell proliferation, migration and adhesion.
  22. 22. 19.03.16 Saradbrata Mishra 2219.03.16 Saradbrata Mishra Some Major Proteoglycan Family Members
  23. 23. 19.03.16 Saradbrata Mishra 23 • Syndecan is a cell surface proteoglycan. • It has a transmembrane core protein with an extracellular side chain and a cytoplasmic tail. • Extracellularly it binds to bFGF (released from damaged ECM) & intracellularly with actin cytoskeleton. • Finally syndecan facilitates interaction with cell surface receptor for FGF. • Thus ECM regulates activity of basic fibroblast growth factor (bFGF, FGF-2) SYNDECAN
  24. 24. 19.03.16 Saradbrata Mishra 2419.03.16 Saradbrata Mishra (5) GLYCOSAMINOGLYCAN • Unbranched polysaccharide chains composed of repeating disaccharide units. • Disaccharide subunits are: 1. uronic acid D-glucuronic acid or L-iduronic acid 2. amino sugar N-acetyl glucosamin (GlcNAc) or N-acetyl galactosamin (GalNAc) • They are negatively charged under physiological conditions (due to the occurrence of sulfate and uronic acid groups).
  25. 25. 19.03.16 Saradbrata Mishra 2519.03.16 Saradbrata Mishra 7 Types of GAGs 1. Hyaluronic acid- The only non sulfated GAG. Found in joint fluid, vitreous body, cartilage. Important in wound healing. 2. Chondroitin sulfate- Tensile strength to cartilage, tendons, ligaments & aortic wall. 3. Dermatan sulfate- Widely distributed troughout the body, mostly skin and blood vessels.
  26. 26. 19.03.16 Saradbrata Mishra 2619.03.16 Saradbrata Mishra Contd.... 4. Heparin- Heparin is mostly intracellular unlike rest of GAGs (e.g. in mast cells). Involved in anticoagulation by binding factor IX, XI and AT-3. Binds lipoprotein lipase in endothelial cell walls and puts them into circulation. 5. Heparan sulfate- Role in developmental processes, angiogenesis, blood coagulation and tumor metastasis. 6. Keratan sulfate type 1 7. Keratan sulfate type 2 Present in cornea, cartilage and bone. In CNS they have role in development and formation of glial scars.
  27. 27. 19.03.16 Saradbrata Mishra 2719.03.16 Saradbrata Mishra (6) FIBRONECTIN • Fibronectin is a large (450 kD) molecule, having 2 forms (extra & intra cellular forms). • Intracellular cytoskeleton will align with the extracellular fibronectin to detemine cell shape. • Fibronectins guide immune cells to wounded areas and thus promote wound healing. • It has a crucial role in wound healing, tissue and plasma fibronectin provide the scaffolding for subsequent ECM deposition, angiogenesis, and reepithelialization. • In the plasma it links to fibrin and helps in blood clotting process. • Helps in cell adhesion, growth, migration, and differentiation. • During cell movement (as during embryogenesis), pathways of fibronectin guide cells to their destinations. • Fibronectin is also found in normal human saliva, which helps prevent colonization of the oral cavity and pharynx by potentially pathogenic bacteria.
  28. 28. 19.03.16 Saradbrata Mishra 2819.03.16 Saradbrata Mishra STRUCTURE OF FIBRONECTIN.... • Fibronectin exists as a protein dimer, consisting of two nearly identical monomers linked by a pair of disulfide bonds • Mainly 2 types 1) Soluble plasma fibronectin- Produced in the liver by hepatocytes. 2) insoluble cellular fibronectin- It is a major component of the extracellular matrix. It is secreted by various cells, primarily fibroblasts. • There are four fibronectin-binding domains, allowing fibronectin to associate with other fibronectin molecules. • The fibrin, heparan and collagen binding domains link it to the ECM. • The integrin binding domain binds to cell membrane by membrane-spanning receptor – integrin through arginine- glycine-aspartic acid (RGD) motifs.
  29. 29. 19.03.16 Saradbrata Mishra 2919.03.16 Saradbrata Mishra (7) LAMININ • Laminin is the most abundant glycoprotein in basement membrane; has binding domains for both ECM and cell surface receptors. • It is an 820-kD cross-shaped heterotrimer that connects cells to underlying ECM components such as type IV collagen and heparan sulfate. • Laminins bind cells to the basal lamina of epithelial and connective tissues, and to their surrounding muscle cells, fat cells, and Schwann cells. • The basal lamina serves as a structural support for tissues and as a permeability barrier to regulate movement of both cell and molecules. • It also modulates primordial germ cell migration during embryogenesis.
  30. 30. 19.03.16 Saradbrata Mishra 3019.03.16 Saradbrata Mishra Contd....
  31. 31. 19.03.16 Saradbrata Mishra 3119.03.16 Saradbrata Mishra Laminin β1 Laminin β2 kidneybasementmembrane
  32. 32. 19.03.16 Saradbrata Mishra 3219.03.16 Saradbrata Mishra Laminins- Primordial germ cell migration
  33. 33. 19.03.16 Saradbrata Mishra 3319.03.16 Saradbrata Mishra (8) INTEGRINS • Also known as The Molecular Glue of Life. • Integrins are a large family of transmembrane heterodimeric glycoproteins (composed of α- and β-subunits) that allow cells to attach to ECM constituents. • The ECM constituents are laminin and fibronectin mostly. • Most integrins are receptors for extracellular matrix proteins. • Intracellularly it links with intracellular cytoskeleton & also with focal adhesion complexes(e.g.vinculin, α actinin and talin) that can recruit and activate tyrosine kinases, that ultimately trigger downstream signaling cascades.
  34. 34. 19.03.16 Saradbrata Mishra 3419.03.16 Saradbrata Mishra Structure of integrin
  35. 35. 19.03.16 Saradbrata Mishra 3519.03.16 Saradbrata Mishra Functions of Integrin • Integrins on the surface of leukocytes are essential in mediating adhesion and transmigration of leukocytes across endothelium at sites of inflammation. • By binding to vWF or fibrinogen,(GPIIb/IIIa) integrin play a critical role in platelet aggregation. • Intracellularly the signaling cascades can influence locomotion, proliferation, survival, apoptosis, shape and differentiation of cells. • Therefore over all 2 functions of integrins are 1) Attachment of the cell to the ECM. 2) Signal transduction from the ECM to the cell.
  36. 36. 19.03.16 Saradbrata Mishra 36 DISEASES RELATED TO DEFECT IN ECM COMPONENTS
  37. 37. 19.03.16 Saradbrata Mishra 37 SCURVY • Acquired disease of fibrillar collagen • Because of the abundance of ascorbic acid in many foods, scurvy has ceased to be a global problem. • Secondary deficiency, particularly among older individuals, chronic alcoholics, people having erratic and inadequate eating patterns, patients undergoing peritoneal dialysis and hemodialysis, infants who are maintained on formulas of evaporated milk, soldiers during war periods. llustration from Man-of-War by Stephen Biesty
  38. 38. 19.03.16 Saradbrata Mishra 38 Contd.... • Vitamin C has function of activation of prolyl and lysyl hydroxylases from inactive precursors, providing for hydroxylation of procollagen.
  39. 39. 19.03.16 Saradbrata Mishra 39 PROGRESSIVE SYSTEMIC SCLEROSIS (SCLERODERMA) • Systemic sclerosis is characterized by triad of: (1) chronic inflammation thought to be the result of autoimmunity, (2) Wide sread vascular damage and (3) progressive interstitial and perivascular fibrosis in the skin and multiple organs. • Fibrosis may be the result of activation of fibroblasts by cytokines produced by T cells, but what triggers T-cell responses is unknown. • A limited form of this disease k/a CREST syndrome 1) Calcification of subcutaneous tissue 2) Raynaud's phenomenon 3) Esophageal dysmotility 4) Sclerodactyly 5) Telangiectasia
  40. 40. 19.03.16 Saradbrata Mishra 40 In SCLERODERMA multisystemic changes are as follows • skin:- Increase in dermal collagen in the dermis, thinning of epidermis, atrophy of dermal appendages, thickening of walls of dermal capillaries. • git:- Rubber-hose like inflexibility of lower third of esophagus, GERD & loss of microvilli in small intestine l/t malabsorption. • joint:- Hypertrophy & hyperplasia of synovial soft tissue. • muscles:- Inflammatory myositis • kidney:- Intimal thickening of interlobular arteries, Htn & renal failure. • lungs:- Interstitial fibrosis & pulmonary hpertension. • heart:- Myocardial fibrosis & pericarditis with effusion.
  41. 41. 19.03.16 Saradbrata Mishra 41 OTHER COLLAGEN VASCULAR DISEASES • Also called as connective tissue diseases. • Immune system causes inflammation in collagen and nearby joints. • Constitute a group of diseases such as Systemic Lupus Erythematosus (SLE) Rheumatoid Arthritis (RA) Sjogren syndrome (SS) Mixed Connective Tissue diseases (MCTD) • All CVDs share some common signs and symptoms. fatigue muscle weakness fever body aches joint pain skin rash
  42. 42. 19.03.16 Saradbrata Mishra 42 OSTEOGENESIS IMPERFECTA (OI) • Also known as brittle bone disease or Lobstein syndrome. • Caused by deficiency of type I collagen. Most cases are caused by mutations in the COL1A1 and COL1A2 genes, • A congenital bone disorder characterized by brittle bones that are prone to fracture. • Also present with shorter height, neurological features including communicating hydrocephalus, basilar invagination, and seizures, blue sclerae, hearing loss etc. • Eight types of OI can be distinguished.
  43. 43. 19.03.16 Saradbrata Mishra 43 OI Types....
  44. 44. 19.03.16 Saradbrata Mishra 44 Ehlers-Danlos Syndromes (EDS) • EDSs comprise a clinically and genetically heterogeneous group of disorders that result from some defect in the synthesis or structure of fibrillar collagen. • EDS is known to affect men and women of all racial and ethnic backgrounds. • There are six distinct types of EDS currently identified. • Each type is thought to involve a unique defect in connective tissue, although not all of the genes responsible for causing EDS have been found. • All share joint laxity, soft skin, easy bruising, and some systemic manifestations.
  45. 45. 19.03.16 Saradbrata Mishra 45 EDS Types....
  46. 46. 19.03.16 Saradbrata Mishra 46 ALPORT SYNDROME (AS) • It comes under the category of hereditary nephritis. • Due to defect in collagen 4 synthesis (α3, α4 & α5 chain) (encoded on both autosomes eg chromosomes 2 & 13 and X- chromosome. • Among them most common is deletion in collagen 4 α5 chain (COL4A5). • In 85% cases females typically presents with only hematuria. • BUT males present with hematuria with a spectrum of s/s eg. nerve deafness, lens dislocation, posterior cataracts, corneal dystrophy etc. • Hematuria is asociated with red cell cast, later on proteinuria and at last nephrotic syndrome developes.
  47. 47. 19.03.16 Saradbrata Mishra 47 AS Contd.... • As the disease progresses there is development of focal segmental and global glomerulosclerosis, vascular sclerosis, tubular atrophy, and interstitial fibrosis. • 90% of males progress to ESRD and renal failure before 40 years od age.  Collagen IV defects can also cause stroke, hemorrhage, porencephaly.
  48. 48. 19.03.16 Saradbrata Mishra 48 EPIDERMOLYSIS BULLOSA DYSTROPHICA (EBD) • It is one of the entities of Non Inflammatory Blistering Disorders. • It usually results from mutations in the COL7A1 gene, which encodes type VII collagen, a major component of the basement membrane anchoring fibrils. • It may follow an autosomal dominant or autosomal recessive mode of inheritance. • At the sites of trauma blisters are formed in the upper dermis followed by scarring.
  49. 49. 19.03.16 Saradbrata Mishra 4919.03.16 Saradbrata Mishra CHONDRODYSPLASIAS • The spondyloepiphyseal dysplasias (SEDs) and spondyloepimetaphyseal dysplasias (SEMDs):- are a heterogeneous group of skeletal dysplasias (dwarfing disorders) characterized by abnormal epiphyses, with and without varying egrees of metaphyseal irregularities, flattened vertebral bodies, and myopia. Due to type- 2 collagen defect. • Schmid metaphyseal chondrodysplasia.:- A type X collagen mutation. • Stickler syndrome (hereditary progressive arthro-ophthalmopathy):- A subtype of collagenopathies, types II and XI Characterized by distinctive facial abnormalities, ocular problems, hearing loss, and joint problems. • Achondroplasia:- Due to mutation in fibroblast growth factor receptor 3.
  50. 50. 19.03.16 Saradbrata Mishra 50 SOME LOCALISED FORM OF COLLAGEN DEPOSITION DEFECT • Peyronie's disease:- Growth of abnormal collagen (Type I & III) in the penis. • Beal's syndrome:- Contractures of hip, knee, elbows and ankle joints. • Hypertrophic scar:- Accumulation of excessive amounts of collagen may give rise to a raised scar. • Keloid:- When the scar tissue grows beyond the boundaries of the original wound and does not regress • Loeys-Dietz syndrome:- Aneurysms in the aorta, often in children.
  51. 51. 19.03.16 Saradbrata Mishra 51 MARFAN SYNDROME • Marfan syndrome results from an inherited (autosomal dominant) defect in an extracellular glycoprotein fibrillin-1. • Most of these are missense mutations that give rise to abnormal fibrillin-1. • skeletal abnormalities:- Unusually tall with exceptionally long extremities; pectus excavatum or a pigeon-breast deformity. • ocular changes:- bilateral subluxation or dislocation of lens. • Cardiovascular lesions:- MVP, dissecting aortic aneurysm. • Clinical diagnosis of Marfan syndrome is currently based on the so called “revised Ghent criteria.”
  52. 52. 19.03.16 Saradbrata Mishra 5219.03.16 Saradbrata Mishra DISEASES RELATED TO LAMININ • Progeria:- (early onset of aging), is possibly due to a defective laminin. • A rare form of congenital muscular dystrophy:- Due to deficiency in Laminin α2 ( mutation in LAMA 2 gene). Presents with proximal muscle weakness leukoencephalopathy, dilated cardiomyopathy, conduction defects, epilepsy etc. • Junctional Epidermolysis bullosa:- Due to defect in laminin 5 & 6 A skin condition characterized by blister formation within the lamina lucida of the basement membrane zone. 3 types have been described 1) JEB with pyloric atresia 2) Herlitz type (lethal during infancy) 3) Non-Herlitz type • Pierson syndrome:- Caused by mutations in LAMB2, the gene encoding the basement membrane protein laminin β2 Congenital nephrotic syndrome accompanied by ocular and neurological defects.
  53. 53. 19.03.16 Saradbrata Mishra 53 Clinical relevance of INTEGRIN • In Bordetella pertussis infection (whooping cough):- The pathogen inactivate G-proteins (linked to integrin) & renders the host's leukocytes incapable of transducing signals. Patients exhibit an impairment in leukocyte transmigration. • GPIIb/IIIa integrin inhibitor is now approved in many countries for symptomatic treatment of acute coronary symptoms. • Leukocyte adhesion deficiency:- LAD1 is most common; due to deficiency of the β-2 integrin subunit (CD18). Presents as recurrent bacterial infections, neutrophilia, delay in umbilical cord sloughing etc. • Glanzmann Thrombasthenia:- Due to defect in β-3 subunit of integrin.
  54. 54. 19.03.16 Saradbrata Mishra 54 clinical relavance of other ECM components • Enzyme collagenase, secreted by Clostridium perfringens causes breakdown of collagen matrix & helps bacterial invasion. • Similarly Hyaluronidase an enzyme secreted by some bacteria(Staphylo/ Strepto/ Pneumococci), which breaks the hyaluronan & helps with their invasion of tissues. • Heparan sulphate serve as cellular receptor for a number of viruses including the respiratory syncytial virus. • In many kinds of cancer, cells unable to make fibronectins loose shape and detach from the ECM to become malignant. • Fibronectin Glomerulopathy:- deposition of protein fibronectin in the glomeruli; l/t proteinuria, renal tubular acidosis, hematuria, along with hypertension eventually resulting in renal failure.
  55. 55. 19.03.16 Saradbrata Mishra 55 RESEARCH ON THERAPEUTICS BY TARGETTING ECM • Integrins represent potential drug targets for cancer therapy because of its role in Epithelial-Msenchymal Transition. • human gene therapy of stem cells have achieved limited success partly because of low gene transfer efficiency. Recent studies show Fragments of fibronectin can be used as a ligand to retrovirus in gene transfer. • Fibronectin promotes VEGF-induced CD34+ cell differentiation into endothelial cells; have clinical potential for endothelialization of prosthetic vascular grafts and revascularization of injured myocardium.
  56. 56. 19.03.16 Saradbrata Mishra 56 Contd.... • LAMC2 (a laminin components) overexpression appears to drive tumorigenesis; thus a potential therapeutic anticancer target for inhibiting tumorigenesis. Furthermore, elevated serum levels of LAMC2 in cancer patients might be a diagnostic biomarker. • Crucial role of β1-integrin in mammary tumor progression, in particular in its metastatic phase, and are of great clinical interest. • Elastin-like polypeptide is a new drug delivery technology that is complementary and synergistic to current drug delivery modalities in cancer chemotherapy.
  57. 57. 19.03.16 Saradbrata Mishra 57 SUMMARY • Components of ECM fall into 3 groups; 1) Fibrous structural proteins:- Provides strength & elasticity 2) Water hydrated gels:- Provides compressive resistance & lubrication 3) Adhesive glycoprotein & adhesion receptor:- Connects ECM elements to cells. • ECM acts as a mechanical support, control cell proloferation, scaffolding for tissue renewal and cellular interaction. • In many autoimmune and genetically inherited diseases the basic pathology lies in different ECM components. • There is a wide area of research for treatment of many incurable diseases including cancers by targetting various ECM constituents.
  58. 58. 19.03.16 Saradbrata Mishra 58