Connective Tissue ProperConnective Tissue ProperConnective Tissue ProperConnective Tissue Proper

Won Taek Lee, M.D., Ph.D.Won Taek Lee, M.D., Ph.D.Won Taek Lee, M.D., Ph.D.Won Taek Lee, M.D., Ph.D.

Connective TissueConnective TissueConnective TissueConnective Tissue

CharacteristicsCharacteristics

1. abundant 1. abundant intercellular substanceintercellular substance

2. diversity of cellular components2. diversity of cellular components

Connective TissueConnective TissueConnective TissueConnective Tissue

ClassificationClassification

Connective Tissue ProperConnective Tissue Proper

Adipose TissueAdipose Tissue

Specialized Connective TissueSpecialized Connective Tissue

Bone and CartilageBone and Cartilage

Blood and Hemopoietic TissueBlood and Hemopoietic Tissue

Connective Tissue ProperConnective Tissue ProperConnective Tissue ProperConnective Tissue Proper

Cellular ComponentsCellular Components

Fixed cellsFixed cells Wandering cellsWandering cells

Intercellular Substance (Matrix)Intercellular Substance (Matrix) FibersFibers Ground substanceGround substance

Cellular ComponentsCellular ComponentsCellular ComponentsCellular Components

1. Fibroblast - Fibrocyte1. Fibroblast - Fibrocyte 2. Macrophage system2. Macrophage system3. Mast cell3. Mast cell4. Plasma cell4. Plasma cell5. Adipose cell5. Adipose cell6. Mesenchymal cell6. Mesenchymal cell6. Others: 6. Others: leukocytes, smooth muscle cell, pericytesleukocytes, smooth muscle cell, pericytes

Fibroblast - FibrocyteFibroblast - FibrocyteFibroblast - FibrocyteFibroblast - Fibrocyte

blastic activity - intercellular substanceblastic activity - intercellular substance

---- protein synthesizing cells in active state---- protein synthesizing cells in active state

limited activity in resting stage (fibrocyte)limited activity in resting stage (fibrocyte)

-blast, -cyte change-blast, -cyte change

osteoblast - osteocyteosteoblast - osteocyte

chondroblast - chondrocytechondroblast - chondrocyte

cementoblastt - cementocytecementoblastt - cementocyte

Fibroblast - FibrocyteFibroblast - Fibrocyte

Fibroblast - FibrocyteFibroblast - Fibrocyte

FibroblastFibroblast

FibrocyteFibrocyte

Function:Function:

Fibers (collaen, elastic)Fibers (collaen, elastic)

and ground substanceand ground substance

(proteoglycan)(proteoglycan)

production.production.

MacrophageMacrophage System SystemMacrophageMacrophage System System

high high phagocyticphagocytic activity activity ---- secondary---- secondary lysosomelysosome precursor cell ---- blood precursor cell ---- blood monocytemonocyte

Mononuclear phagocytic system (MPS)Mononuclear phagocytic system (MPS) CTP ----------CTP ---------- histiocytehistiocyte liver ----------liver ---------- Kupffer cellKupffer cell lung ----------lung ---------- dust cell (alveolar macrophage)dust cell (alveolar macrophage) bone ---------bone --------- osteoclastosteoclast CNS ---------CNS --------- microgliamicroglia Placenta -----Placenta ----- Hofbauer cellHofbauer cell

MacrophageMacrophage

Mast CellMast CellMast CellMast Cell

Large cell, 20-30 Large cell, 20-30 m in diameterm in diameter

with small nucleus,with small nucleus, filled with abundantfilled with abundant secretory granulessecretory granules prominent Golgiprominent Golgi

Secretory Secretory (metachromatic)(metachromatic) granule granule

0.3-0.5 0.3-0.5 m in diameterm in diameter storage of chemical mediators of storage of chemical mediators of immediate type immune responseimmediate type immune response metachromasiametachromasia due to due to heparinheparin and other and other glycosaminoglycansglycosaminoglycans

Mast CellMast Cell

Mast CellMast Cell

Mast Mast

CellCell

degranulationdegranulation

IgEIgE

Plasma CellPlasma CellPlasma CellPlasma Cell

AntibodyAntibody (Ab)(Ab) producing cellproducing cell Protein synthesizing cellProtein synthesizing cell cart wheel (clock face)cart wheel (clock face) appearanceappearance ------ chromatin pattern------ chromatin pattern cytoplasmic cytoplasmic basophiliabasophilia ------ abundant rER------ abundant rER perinuclear halo perinuclear halo ----- Golgi complex----- Golgi complex Chronic inflammatory cellChronic inflammatory cell humoralhumoral immune response immune response Precursor cellPrecursor cell ----- ----- B lymphocyteB lymphocyte

Plasma CellPlasma Cell

Plasma CellPlasma Cell

Adipose (Fat) CellAdipose (Fat) CellAdipose (Fat) CellAdipose (Fat) Cell

WhiteWhite (unilocular)(unilocular) adipose cell adipose cell 20-100 20-100 m in diameterm in diameter single central single central lipid dropletlipid droplet peripheral nucleusperipheral nucleus signet ring cellsignet ring cell

BrownBrown (multilocular)(multilocular) adipose cell adipose cell 15-25 15-25 m in diameterm in diameter abundant abundant mitochondriamitochondria and and lipid dropletlipid droplet heat generationheat generation

White Adipose (Fat) CellWhite Adipose (Fat) Cell

White Adipose White Adipose

(Fat) Cell(Fat) Cell

Brown Adipose Brown Adipose

(Fat) Cell(Fat) Cell

NorepinephrineNorepinephrine

Adenyl cyclase activationAdenyl cyclase activation

Lipase activationLipase activation

Fatty acids releaseFatty acids release

Oxidation in mitochondriaOxidation in mitochondria

Heat generationHeat generation

Brown Adipose Brown Adipose

Cell FunctionCell Function

Mesenchymal CellMesenchymal CellMesenchymal CellMesenchymal Cell

small stellate cell small stellate cell 7-10 mm in diameter7-10 mm in diameter not easily distinguished from fibrocytenot easily distinguished from fibrocyte

Pluripotential (totipotential) stem cellPluripotential (totipotential) stem cell precursor of connective tissue cellprecursor of connective tissue cell of embryonic of embryonic mesenchymemesenchyme small population of cells of mesenchymesmall population of cells of mesenchyme persist into postnatal life and persist into postnatal life and differntiate to form other CT cellsdifferntiate to form other CT cells

Mesenchymal Mesenchymal

CellCell

Connective Tissue FiberConnective Tissue FiberConnective Tissue FiberConnective Tissue Fiber

1. Collagen fiber ----1. Collagen fiber ---- type I collagentype I collagen

2. Reticular fiber ----2. Reticular fiber ---- type III collagentype III collagen

3. Elastic fiber -------3. Elastic fiber ------- elastin, fibrillinelastin, fibrillin

Collagen FiberCollagen FiberCollagen FiberCollagen Fiber

• AcidophilicAcidophilic thick, birefringent thick, birefringent• Very resistant to tractionVery resistant to traction

- extensibility ---- 5%- extensibility ---- 5%

- very high - very high tensile strengthtensile strength

• Most abundantMost abundant proteins of the body proteins of the body - 30-35% of dry body weight- 30-35% of dry body weight - 20% of total body proteins- 20% of total body proteins

• High in glycine, alanine, proline,High in glycine, alanine, proline, hydroxyproline, hydroxylysinehydroxyproline, hydroxylysine poor in sulfur, no tryptophanpoor in sulfur, no tryptophan

Collagen FiberCollagen Fiber

dermisdermis

Collagen FiberCollagen Fiber

• Collagen fiber bundleCollagen fiber bundle

Collagen Fiber --------------------------- Collagen Fiber --------------------------- 5-15 5-15 mm

Collagen Fibril ------------------------ Collagen Fibril ------------------------ 0.3-2 0.3-2 mm

Collagen Microfibril -------------- Collagen Microfibril -------------- 5-20 nm5-20 nm

Collagen Protofibril ------------ Collagen Protofibril ------------ 4.5 nm4.5 nm

Tropocollagen Molecules - Tropocollagen Molecules - 1.5 nm1.5 nm

• Periodicity of Collagen FibrilsPeriodicity of Collagen Fibrils

- longitudinal arrangement of tropocollagen molecules- longitudinal arrangement of tropocollagen molecules

0.6 D (38.4 nm) gap --- lacunar region0.6 D (38.4 nm) gap --- lacunar region

- stepwise arrangement- stepwise arrangement

overapping region --- ~10% of tropocollagen length overapping region --- ~10% of tropocollagen length

Collagen FibrilsCollagen Fibrils

Collagen SynthesisCollagen Synthesis

Intracellular ProcessIntracellular Process

Nucleus --------Nucleus -------- mRNA transcription mRNA transcription

Ribosome -----Ribosome ----- transcription of preprocollage transcription of preprocollage

nn rER cisterna --rER cisterna -- hydroxylation and glycosylatio hydroxylation and glycosylatio

n, n, formation of procollagen triple helix formation of procollagen triple helix

Golgi ------------Golgi ------------ secretion of procollagen secretion of procollagen

Extracellular ProcessExtracellular Process

Propeptidase convert procollagen toPropeptidase convert procollagen to

tropocollagentropocollagen

Process of Process of

Collagen SCollagen S

ynthesisynthesis

Major Collagen TypesMajor Collagen Types

Type Procollagen morphology Tissue Distribution Disease

I [1(I)]2 2(I)] fiber (collagen)

bone, skin, tendon, ligament, dentin, cementum

osteogenesis imperfecta

II [1(II)]3 fiber cartilage chondrodysplasia

III [1(III)]3fiber (reticula

r)

skin, arteries, reticular tissues and organs, liver

Ehlers-Danlos syndrome type IV

IV [1(IV)]2 2(IV)] sheet basement membrane Alport's syndrome

V [1(V)]2 2(V)] fiberfetal tissues, placenta, interstitial tissues

VII [1(VII)]3anchoring fibr

iljunction of epidermis and dermis

epidermolysis bullosa

Collagen Types Collagen Types

Type I collagen Type I collagen Type IV collagenType IV collagen

Collagen defectsCollagen defects ScurvyScurvy – deficiency of Vitamine C, – deficiency of Vitamine C,

cofactor for proline hydroxylasecofactor for proline hydroxylase Ehlers-DanlosEhlers-Danlos syndrome syndrome typetype VIVI – – faulty lysyl hydroxylation, kyposcoliosis faulty lysyl hydroxylation, kyposcoliosis

Ehlers-DanlosEhlers-Danlos syndrome syndrome typetype IVIV – – defects in type III collagen, vascular abnormalities defects in type III collagen, vascular abnormalities Ehlers-DanlosEhlers-Danlos syndrome syndrome typetype IVIV – – defects in procollagen peptidase, articular abnormalities defects in procollagen peptidase, articular abnormalities Osteogenesis imperfectaOsteogenesis imperfecta – type I collagen gene mutation – type I collagen gene mutation

ChondrodysplasiaChondrodysplasia – type II collagen gene mutation – type II collagen gene mutation

Alport’s syndromeAlport’s syndrome – type IV collagen (BM) anomaly – type IV collagen (BM) anomaly

Collagen excess: Collagen excess: Fibrosis, Kelloid, CirrhosisFibrosis, Kelloid, Cirrhosis

ScurvyScurvyVitamine C (cofactor for proline hydrVitamine C (cofactor for proline hydr

oxylase) Deficiencyoxylase) Deficiency

Scurvy – Historical diseaseScurvy – Historical diseaseJames LindJames Lind(1716-1794)(1716-1794)

Ehlers-Danlos syndromeEhlers-Danlos syndrome

Defects in collagen synthesis – High elasticityDefects in collagen synthesis – High elasticity

Osteogenesis ImperfectaOsteogenesis Imperfecta

Alport’sAlport’s

syndromesyndrome

Reticular FiberReticular FiberReticular FiberReticular Fiber

• Argyrophilic, PAS-positive, thin (0.5-2 m) fiberArgyrophilic, PAS-positive, thin (0.5-2 m) fiber

Structural maintenance in expansile organ.Structural maintenance in expansile organ.

• Type III CollagenType III Collagen

6-12% hexoses (1% in collagen type I)6-12% hexoses (1% in collagen type I) Collagen microfibrils + Proteogycan interfibrillar bridgeCollagen microfibrils + Proteogycan interfibrillar bridge

• Immature FiberImmature Fiber

Abundant in embryonic tissues and wound healingAbundant in embryonic tissues and wound healing

• Reticular Tissue, Glands, Large Vessels, Intestinal WallReticular Tissue, Glands, Large Vessels, Intestinal Wall

• Ehlers-DanlosEhlers-Danlos TypeType IVIV (Faulty transcription/translation of (Faulty transcription/translation of Type III Collagen)Type III Collagen)

Reticular FiberReticular Fiber

Elastic FiberElastic FiberElastic FiberElastic Fiber

• 0.1-10 0.1-10 m thick fiberm thick fiber

• High Elasticity (rubber-like consistency)High Elasticity (rubber-like consistency)

• Special stain: resorcin fuchsin, aldehyde fuchsin, Special stain: resorcin fuchsin, aldehyde fuchsin,

van Gieson (mordant hematoxylin), and orceinvan Gieson (mordant hematoxylin), and orcein

• Distribution: Elastic Connective TissueDistribution: Elastic Connective Tissue

ligamentum nucha, ligamentum flavaligamentum nucha, ligamentum flava

vocal ligaments, stylohyoid ligementvocal ligaments, stylohyoid ligement

elastic membrane and lamellae of arteryelastic membrane and lamellae of artery

elastic cartilageelastic cartilage

Elastic FiberElastic FiberElastic FiberElastic Fiber

Elastin, central (Pars Amorpha)Elastin, central (Pars Amorpha)

glycine (half), proline (10%), hydroxyprolineglycine (half), proline (10%), hydroxyproline

desmosine, isodesmosinedesmosine, isodesmosine

Microfibrils, peripheral (Pars Filamentosa)Microfibrils, peripheral (Pars Filamentosa)

11-13 nm in diameter11-13 nm in diameter

Fibrillin: Fibrillin:

no isodesmosine, desmosine, hydroxyprolineno isodesmosine, desmosine, hydroxyproline

half-cystine residue, 5% neutral sugarhalf-cystine residue, 5% neutral sugar

Oxytalan FiberOxytalan Fiber

microfibrilmicrofibril no elastinno elastin

Elaunin FiberElaunin Fiberelastin depositionelastin deposition

microfibrilmicrofibril

Elastic FiberElastic Fiber

elastin, centralelastin, centralmicrofibril, peripheralmicrofibril, peripheral

Elastic Fiber EvolutionElastic Fiber Evolutionoxytalan

fiber

elauninfiber

elasticfiber

Elastic FiberElastic Fiber

Elastic Fiber Elastic Fiber central elastin and peripheral microfibrilscentral elastin and peripheral microfibrils

Elastic Elastic

Fiber Fiber

stretch stretch andand

relaxationrelaxation

elasticityelasticity

Defects in Fibrillin – Marfan syndrome Defects in Fibrillin – Marfan syndrome

tall statuetall statue

arachnoidactilyarachnoidactily

Defects in Fibrillin – Marfan syndrome Defects in Fibrillin – Marfan syndrome

Marfan syndrome Marfan syndrome

PharaohPharaoh Akhenaten Akhenaten Abraham LincolnAbraham Lincoln

Ground SubstanceGround SubstanceGround SubstanceGround Substance

ProteoglycanProteoglycan glycosaminoglycan (GAG)glycosaminoglycan (GAG)

made of repeating disaccharide made of repeating disaccharide hexose+hexosaminehexose+hexosamine core poteincore potein test tube brush shapetest tube brush shape sometimes linked tosometimes linked to hyaluronic acidhyaluronic acid

Structural GlycoproteinStructural Glycoprotein fibronectin, laminin, chondronectinfibronectin, laminin, chondronectin

GAG hexuronic acid hexosamine Distribution

hyaluronic acid

D-glucuronic acid D-glucosaminecartilage, umbilical cord, synovial fluid, vitreous humor

chondroitin-4-sulfate

D-glucuronic acid D-galactosaminecartilage, bone, cornea, skin, notochord, aorta

chondroitin-6-sulfate

D-glucuronic acid D-galactosaminecartilage, umbilical cord, skin, aorta (media)

dermatan sulfate

L-iduronic acid, D-glucuronic acid

D-galactosamineskin, tendon, aorta (adventitia)

heparan sulfate

D-glucuronic acid, D-iduronic acid

D-galactosamineaorta, lung, liver, basal lamina

keratan sulfate (corneal)

D-galactose D-galactosamine cornea

keratan sulfate (skeletal)

D-galactose D-glucosaminecartilage, nucleus pulposus, annulus fibrosus

Glycosaminoglycans (GAG)Glycosaminoglycans (GAG)

Proteoglycan and Glycosaminoglycans (GAG)Proteoglycan and Glycosaminoglycans (GAG)

Structural GlycoproteinStructural GlycoproteinStructural GlycoproteinStructural Glycoprotein

Fibronectin LamininFibronectin Laminin

fibronectinfibronectin

integrinintegrin

interactioninteraction

Extracellular and Extracellular and

intracellularintracellular

integrityintegrity

Extracellular Matrix and Cellular InteractionExtracellular Matrix and Cellular Interaction

Connective Tissue ProperConnective Tissue ProperConnective Tissue ProperConnective Tissue Proper

ClassificationClassification

Loose connective tissueLoose connective tissue

Dense connective tissueDense connective tissue

dense regular connective tissuedense regular connective tissue

dense irregular connective tissuedense irregular connective tissue

Loose Connective TissueLoose Connective Tissue

Dense Irregular Connective TissueDense Irregular Connective Tissue

Dense Regular Connective TissueDense Regular Connective Tissue