EXTRACELLULAR MATRIX

SRY SURYANI WIJAYA

EXTRACELLULAR MATRIX (ECM)

• Referred as Connective Tissue• ECM contains 3 major classes of

biomolecules:– Structural proteins : collagen,elastin,fibrillin– Specialized proteins : fibrillin,fibronectin,laminin– Proteoglycans : Glycosaminoglycans (GAGs)ECM plays important roles in

development,inflammatory states,spread of cencer cells.

Collagen

– Major component of most connective tissue– Constitutes approximates 25 % of the protein of

mammal.Collagen type I

- All collagens triple helical structure.- Glycine residues at every third position of triple helical portion of the α –chain.

-Gly-X-Y absolute requirement for the formation of triple helix.

• X proline confer rigidity on • Y hydroxyproline collagen molecule.

• Collagen fibers : stabilized by the formation of covalent-cross link,both within and between the triple helical units. (through the action of lysyl oxidase). Important for the tensile strength of fibers.

• Types of collagen and their genes.• Classification of collagens,based on the

structure they form.

Synthesis of collagen

• Newly synthesized collagen extreme post translational modification before becoming part of a mature extracellular collagen fibers.

• Collagen syntesized in ribosome precursor preprocollagen cleavage of signal peptide hydroxylation of prolyl residues and some lysyl residues.Glycosylation of some hydroxylysyl residues. Formation of triple helix secretion to ECM

• Collagen relatively stable.• Break down during starvation,inflammatory.

• Genetic diseases from abnormalities in the synthesis of collagen.

• Scurvy def vit C affects structure of collagen.

• Major signs bleeding gums,subcutaneus hemorr,poor wound healing.

Elastin

• Responsible for extensibility & elastic recoil in tissues.

• Eg : lung,large Arterial blood vessels,some elastic ligaments ( large amount)

• Skin,ear cartilage ( smaller amounts)

• Williams syndrome• Deletions in the elastin gene.• Developmental disorder affecting tissue and connective

tissue,CNS• Supravalvular aortic stenosis.

• Scleroderma accumulation of elastin• Fragmentation /elastin pulmonary

emphysema,aging of the skin and cutis laxa.

• Major difference between collagen and elastin

Fibrillin

• Large glycoproten 350 kDa.• Structural component of microfibril.• Mutationsa in the gen for fibrillin:– Marfan syndrome :• Inherited disease.• Autosomal dominant• Affect eyes (dislocation of lens)• Skeletal system

tall,arachnodactyly,hyperextensibility of the joints.

• Cardiovascular system• Mutations in the gene (chromosome 15)

• Fibronectin• Major comp of ECM• Aalso found in soluble form in plasma.• Involved in cell adhesion and migration.

• Laminin• Major prot comp of renal glomerulus & other basal

lamina.

• Proteoglycans & Glycosaminoglycans.• There are at least 7 GAGs:

• Ha,cs,ks I & II,heparin,heparan sulfat,dermatan sulfat.

• Mucopolysaccharidoses• Inborn error of metabolisme• Def of enzyme that degrade GAGs

• Mucolipidosis combine features of mucopolysaccharidase & spongiolipidosis

Proteoglycans and GAGs

• Hyaluronic acid• Play an important role in permiting cell migration

during morphogenesis and wound repair.

• Chondroitin sulfates• Maintain shape• Located at sites of calcification in endothelial

bone,cartilage

• Keeratan sulfate I & dermatan sulfate• Present in cornea• Also in cartilage.

• Heparin• An important anticoagulant• Binds with factors IX & XI,but its most important

interaction with antithrombin III.

• Function of GAGs and proteoglycans.

Bone mineralization

• Bone is a mineralized connective tissue disease.

• Contain organic and inorganic material.• Principal protein : type I collagen (90-95 % of

the organic material).• Type V collagen :small amount.

• Inorganic material : hydroxypaptite, sodium,magnesium,carbonate,fluoride.

• 99 % body’s calsium is contained in bone.• Bone dynamic structure,remodeling

(osteoblast and osteoclast) adapt to both physical and hormonal signals.

• Osteoclasts• Multinucleated cells derived fr pluripotent

hematopoetic stem cells.• Bone resorption

• Osteoblast• Mononuclear cells derived fr pluripotent mesenchymal

precursor.• Synthesized most of the proteins found in bone,growth

factors and cytokines• Deposition of new bone matrix• Contarolled mineralization : regulation passage of

calsium and phosphate ion across surface membrane.

• Regulations of bone metabolism– Stimulate osteoblast : parathyroid hormone– Inhibit : steroid hormone.– Stimulate osteoclast : parathyroid hormone– Inhibit : calcitonin and estrogen.

• Metabolic & genetic disorders involve bone.– Osteogenesis imperfecta.

Brittle bone,thin sclera anad translucent,may appear blue (owing to def of connective tissue ).

Mild,extensive,severe and variable.Extensive : occur in the new born90 % mutations in COL1A1 and COL1A2 genes,encoding proα1(I)

and proα2(I) chains.

• Osteopetrosis• Marble bone disease• Increased bone density (inability to resorb bone)• Mutation in the gene (8q22)• Carbonic anhdrase II def normal bone resorption

does not occur.

• Osteoporosis– Generalized progressive reduction in bone mass

tissue per unit volume causing skeletal weakness– Fracture occur easily.– Estrogen and interkleukin-1.

• Chondrodysplasia• Mixed group of hereditary disorders affecting cartilage.• Short limbed dwarfism and numerous skeletal deformities.• Mutations in COL2A1 gene abn collagen type II

Stickler syndrome (deg of joint cart and vitreous body of the eye).

• The best known of chondrodysplasia is ACHONDROPLASIA inherited,autosomal dominant,new mutation.

• Achondrodysplasia is not a collagen disorder but due to mutation of gene encoding FGR3 .

• FGR3 : affect the growth of differentiation of cells of mesenchymal and neuroectodermal origin.