I. Connective Tissues!- Functions: protect, connect, and support other tissues!- Components: !- Extracellular matrix! - Fibers: collagen and elastic fibers!- Ground substance: GAGs, proteoglycans, adhesive glycoproteins!- Cells: fibroblast, adipocyte, macrophase, plasma cell, and mast cell!- From mesenchymal and hemopoietic precursors!- Diff. classes bases on arrangement and abundance of fibers and ground substance!- dense irregular - dense regular - loose (areolar) - adipose - reticular tissue - mucous (embryonic)! II. ECM Fibers A. Collagen: many (29) diff. types, collagen I= most abundant!- flexible inelastic fibers w/high tensile strength!- collagen I: regular or irregular bundles in dense CT!- Synthesized by fibroblasts= most abundant CT cell!- Structure: 3 alpha chains arranged in a triple helix--> make up tropocollagen--> trop. lines up arranged w/spaces between them (leads to striated appearance) --> long tropocollagen arrays= Collagen fibrils--> aggregated to form collagen fibers--> collagen bundles - alpha chain= repeating Gly-Pro-X (gly in middle of helix) - Synthesis: syn. in ER as procollagens-->modification-->intracellular processing (hydroxylation, glycosylation, and form triple helix)-->extracellular processing (proteolysis of the the end peptides-->spont. assembly of the tropocollagen into fibrils, cross-linking by lysine oxidase)-->fibrils bind w/each other and other proteins-->form fibers--> form bundles!- Many diseases due to defects in collagen assembly and prcoessing: muts in processing enzymes, collagen genes, nutritional deficiencies (Scurvy), defects in collagen fibers--> many CT defects !- Note: Azan stain stains collagen blue!- Know 5 collagens: types I, II, III, IV, and VII!I. resists tension, abundant in dermis, fascia, bone, ligaments, and tendons!II. resists pressure, forms fibrils not fibers,found in cartilage!III. structural framework, forms fine reticular fibers in skin, blood vessels, glands, and lymphoid tissue, !IV. forms meshwork, found in basal and external laminae of epithelia, muscle, fast and nerve!VII. forms anchoring fibrils, anchor epithel layers to CT!- Reticular fibers- made of type III collagen fibrils + glycoproteins, stain black by silver stain, lie below basal lamina, support and binds cells, thinner than col. I!- Collagen type IV= major comp. of basal laminae and external laminae!- Don't assemble into fibrils, form an open 2D scaffold network!- Beneath epithelia= basement membrane= basal lamina + reticular lamina (RL has fibers of col. I and III + minor collagen types)!!B. Elastic fibers--> form fibers of varying thickness + lamellar layers of blood vessels!- Give connective tissue elasticity!- Found in blood vessels, skin, and lung!- Core= elastin protein + outer layer of microfibrils (these stain a little bit)!- Elastin has many hydrophobic aa's--> so when stretched they avoid aq. envi-->refold when tension is released= elasticity! Also refolds due to interchain crosslinks!- 75% hydrophobic residues! (Gly, Val, Ala) and very insoluble!- elastin is encoded by 1 gene, alternative splicing -->tropoelastin isoforms!- Synthesis: tropoelastin (soluble precursor) made by smooth muscle ccells, endothelial cells, fibroblasts, and chromdrocytes!- Elastin doesn't like stain, but will stain black w/ Verhoeff stain - Problems: Marfan syndrome, William's syndromeIII. Ground substance A. - Includes: GAGs, proteoglycans, proteoglycan aggregates, and adhesive glycoproteins - = a hydrated gel where the ECM fibers are embedded!- Major component of the ground substance= proteoglycans (a class of glycoprotein)!- Contain glycosaminoglycans (GAGs)= very negatively charged polysaccs (side chains)!- Chain of repeated disaccharides (one sugar= uronic aic, other sugar= amino sugar, of which many are sulfated)!- Bind many physio. imp. cations (K+, Na+, Ca++), bind water-->makes ground substance hydrated and viscous)!- hyaluronic acid (a single, long GAG chain), non-covalently binds many proteoglycan monomers together--> forms a proteoglycan aggregate - this aggregate occupies a large space in hydrated ECM, can bind collagen fibers to maintain gel.!- some bacteria release hyaluronidase= enzyme that breaks down ECM!- proteoglycan monomer= single polypeptide + covalently attached GAGs!- Negative charge of proteoglycans --> interaction w/a variety of extracellular molecules!- Can bind growth factors and signaling molecules--> change the distribution and local concentration gradients of the molecules!!B. Adhesive Glycoproteins (also found in ground substance) Two for today = fibronection + laminin!- Found in small amounts, but widely distributed. !- Imp.. in binding ECM fibers + cells together!- Fibronection= large, multifunctional protein, widely found in ECM!- has recognition sites for cell surface receptors, GAGs, collagens. These sites= domains (distinct protein regions) on fibronection.!-RGD site= binding site for integrins - Integrins= a cell surface receptor for fibronectin and other ECM components!- Dimer of alpha and beta chain!- the specificity of this dimer determines what ECM components to bind to!- a transmembrane protein: cytoplasmic domain that links to the cytoskeleton + enzymes,thus can reg. cell behaviors!- Defects-->diseases (ex. leukocyte adhesion deficiency) - Laminin = an adhesive glycoprotein that's found in basal laminae (sheet in EM) and external laminae (surround muscle cells) (lam.= specialized sheets of extracellular matrix that separate cells from supporting tissue)!- have many sites/specialized domains for binding integrins!- recog. of laminin by cell surface integrins binds the cells to the basal laminae!- The metastatic movement of cancer cells depends on these cell surface integrins, interaction with adhesive glycoproteins, and cell movements thru the basal laminae and along ECM fibers !!!!!!!!!IV. Cells of the ECM A. Cells of the ECM develop from mesenchymal and hemopoietic precursors or stem cells!- the sources persist thru adult life!B. Fibroblasts - synthesize most of type 1 collagen + other ECM comps!- can regenerate and migrate to where they're needed (ex. wound sites)!- fibrocytes= dormant, synthetically inactive fibroblasts, also circulating fibroblasts!- specialized to produce diff. ECM comps in diff. areas of the body!- Recruited to deal with injury, 3 pathways!1) Migration of local fibroblasts (50%)!Laminin assembly2) Recruitment and differentiation into mature fibroblasts from circulating
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