EFFECTS OF DISEASE, ON CONNECTIVE TISSUE            By    Dr. Mohyman Sarfraz
INTRODUCTION TO                            CONNECTIVE TISSUEAlso known as the supporting tissue.1. These tissues connect a...
FUNCTIONS OF CONNECTIVE                              TISSUE1.   Provision of structural support2.   Role as medium for exc...
CELLS OF CONNECTIVE TISSUE1.   Resident cells, which develop and remain within the connective tissue     (fibroblasts, adi...
EXTRACELLULAR MATRI X OF                          CONNECTIVE TISSUE1.   At submicroscopic level, extracellular matrix is a...
FIBRES OF CONNECTIVE TISSUELong slender proteins. Three major types are present namely;1.   Collagen fibers2.   Reticular ...
THE ELASTIC FIBER SYSTEMThe elastic fiber system, is composed of three types of fibers, namely, oxytalan, elaunin andelast...
A.    BUNDLES   OF    ELASTIC    MICRO    FIBRILS   (OXYTALAN)     IN   ZONULE,B. DEVELOPING ELASTIC FIBER WITH CORDS OF A...
The elastic fiber system, by using different proportions of micro fibrils andelastin, constitutes a family of fibers whose...
ELASTIN MOLECULES AREJOINED BY COVALENT BONDSTO GENERATE AN EXTENSIVECROSS-LINKED    NETWORK.BECAUSE    EACH  ELASTINMOLEC...
PATHOLOGY OF ELASTINThe arteries need to be elastic, the skin needs to be elastic all soft tissues need some recoil.      ...
Compared with rubber threads, elastin can stretch at least 5 times more, but intissues they cant reach that limit, because...
GENETIC DEFECTS AFFECTING                              ELASTIC FIBERSMARFAN SYNDROME;                                Marfa...
The media shows a slit (low power) which corresponds to the separation of the layersdue to mucoid degeneration of the conn...
MMP’S?
TRIVIAMatrix metalloproteinases (MMPs) are zinc-dependent endopeptidases;other family members are adamalysins, serralysins...
CUTIS LAXA                                (ELASTOLYSIS)group of rare connective tissue disorders in which the skin becomes...
PATHOPHYSIOLOGYIn most cases of cutis laxa, the biochemical and molecular basis of the skinchanges are unclear. However, t...
1. Lysyl oxidase;                      a copper-dependent enzyme, is important in the synthesis andcross-linking of elasti...
C. SPARSE MIXED PERIVASCULARINFILTRATE     (H/E    STAIN)D. COMPLETE LOSS OF ELASTICFIBERS     (ELASTIN  STAIN)BOTH IN X20
ACQUIRED DEFECTS OF ELASTINElastin is particularly sensitive to aging, and elastogenesis in the skin isaffected by sunligh...
NORMAL VESSEL MORPHOLOGY
SOLAR ELASTOSIS                          (DERMATOHELIOSIS)Sun worshippers disease, Can affect everyones face after the age...
PATHOPHYSIOLOGYA much-cited hypothesis focuses on degradation of collagen fiber bykeratinocyte- and fibroblast-derived mat...
HISTOPATHOLOGY              OF(A)   NORMAL   SKIN        AND(B)   PHOTO   AGED        SKIN. PHOTO     AGED    SKIN     ,IS...
TYPICAL REDNECK
EMPYSEMARecall the structure of lung, which is divided ina. Myriads of microscopic air spaces(alveoli) purpose?Emphysema i...
PATHOGENESISThe walls between the alveoli tend to break down, so that the air spacesbecomes larger and larger and the surf...
PROTEOGYLCANSGlycosaminoglycans (originally called acid mucopolysaccharides) arelinear polysaccharides formed by repeating...
PROTEOGLYCANS CONTAIN ACORE OF PROTEIN (VERTICALROD IN DRAWING) TO WHICHMOLECULES                 OFGLYCOSAMINOGLYCANS (GA...
The proteoglycans are composed of a core protein associated with the four mainglycosaminoglycans: dermatan sulfate, chondr...
In addition to acting as structural components of the extracellular matrix andanchoring cells to the matrix, both extracel...
PATHOLOGY OF PROTEOGLYCANSOSTEOARTHRITIS (DEGENERATIVE ARTHRITIS);                                                        ...
PATHOGENESISEven though osteoarthritis has always been classified as a noninflammatoryarthritis, increasing evidence has s...
PRESSURE AREASGreater loss of joint space occurs at those areas subjected to the greatestpressures. Erosion of the damaged...
NON-PRESSURE AREASAt nonpressure areas along the articular margin, vascularization ofsubchondral marrow, osseous metaplasi...
MEDIAL COMPARTMENT WITH FULL-THICKNESS ARTICULAR CARTILAGELOSS AT BOTH FEMORAL AND TIBIALASPECTS, EXPOSING THE PINKVASCULA...
THIS 3D GRAPHIC REPRESENTATIONDEMONSTRATES      THE    DENSELYPACKED    LARGE    PROTEOGLYCANAGGREGATES "TRAPPED" BETWEENT...
ARTICULAR CARTILAGE. THE LOSS OF PROTEOGLYCANS RESULTS IN DECREASED METACHROMASIA OF THE CARTILAGE.THIS ACCOUNTS FOR THE E...
MYXEDEMA                            (MUCOUS EDEMA)The term myxedema has been applied to several clinical entities and is o...
Myxedema coma/crisis occurs most commonly in older women with long-standing, undiagnosed or undertreated hypothyroidism wh...
PATHOGENESISThe increased deposition of glycosaminoglycan is not fully understood, howevertwo mechanisms predominate.1. Ex...
AT HIGHER POWER OFTHE     SAME    LESION,SPINDLED-TO-STELLATEFIBROBLASTS      FLOATWITHIN THIS MYXOIDSTROMA. CYTOLOGICALAT...
MOHYMAN ET AL SPECIAL THANKS TO LIPTON YELLOW LABEL.
Effects of disease, on connective tissue
Effects of disease, on connective tissue
Effects of disease, on connective tissue
Effects of disease, on connective tissue
Effects of disease, on connective tissue
Effects of disease, on connective tissue
Effects of disease, on connective tissue
Effects of disease, on connective tissue
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Effects of disease, on connective tissue

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Effects of disease, on connective tissue

  1. 1. EFFECTS OF DISEASE, ON CONNECTIVE TISSUE By Dr. Mohyman Sarfraz
  2. 2. INTRODUCTION TO CONNECTIVE TISSUEAlso known as the supporting tissue.1. These tissues connect and support other tissues of the body.2. Characterized by presence of relatively fewer cells but a large amount of extracellular matrix, which consists ofA. Ground substance*Anionic macromolecules{proteoglycans and glycosaminoglycans}and *Multi adhesive glycoproteins{laminin, fibronectin}B. Fiber(proteins){collagen, reticular and elastic}4. Different types of connective tissue differ from each other in cell variety, inchemical composition of ground substance and in number and types of fiberspresent in the extracellular matrix.
  3. 3. FUNCTIONS OF CONNECTIVE TISSUE1. Provision of structural support2. Role as medium for exchange3. Role in defense and protection of the body which is accomplished bya. The intracellular substance of connective tissues acts as a physical barrier to those bacteria which manage to penetrate the epithelial membraneb. Some connective tissue cells have ability to engulf bacteria and other unwanted particulate matter, andc. Some connective tissue cells produce antibodies which react with and inactivate the antigens.4. Storage of fat.
  4. 4. CELLS OF CONNECTIVE TISSUE1. Resident cells, which develop and remain within the connective tissue (fibroblasts, adipocytes and mesenchymal stem cells)2. Migrant cells, which enter the connective tissue from the blood stream(macrophages, plasma cells, mast cells and varieties of white cells{leukocytes}).
  5. 5. EXTRACELLULAR MATRI X OF CONNECTIVE TISSUE1. At submicroscopic level, extracellular matrix is a thick jungle of molecules. Composed of ground substance and fibers.GROUND SUBSTANCE; Amorphous gel like, high in water content, whichnaturally acts as a medium of transport. The ground substance of C.T iscomposed of:1. Glycosaminoglycans(long chain polysaccharide)2. Proteoglycans(core protein i.e. polypeptide, to which molecules of sulfated glycosaminoglycans are covalently bound)3. Glycoproteins(adhesive glycoproteins, since fasten various components of C.T with each other. { chondroitin in cartilage and osteonectin in bone}).
  6. 6. FIBRES OF CONNECTIVE TISSUELong slender proteins. Three major types are present namely;1. Collagen fibers2. Reticular fibers3. Elastic fibers system(oxytalin, elaunin and elastic)The first two (collagen and reticular) are made up of protein collagen,whereas the elastic fibers are made up of the protein elastin.
  7. 7. THE ELASTIC FIBER SYSTEMThe elastic fiber system, is composed of three types of fibers, namely, oxytalan, elaunin andelastic. The structures of the elastic fiber system develop through three successive stages,differentiated by the amount of the protein elastin that exists in each type of fiber. Oxytalan(gr. Oxy, thin)fibers can be found in the zonulefibers of the eye and where the dermis connects the elastic system to the basal lamina.Oxytalanic fibers are not elastic—they do not contain the protein elastin—but they arehighly resistant to pulling forces. They consist of a bundle of 10-nm micro fibrilscomposed of various glycoproteins, including fibromodulin I and II and a large moleculecalled fibrillin. In the second stage of development, an irregular depositionof the protein elastin appears between the oxytalan fibers, forming the elaunin (Gr.elaunem, to drive) fibers. The elaunin fibers contain a mixture of elastin and micro fibrilswithout any preferential orientation. These structures are found around sweat glands and inthe dermis. During the third stage of development, elastin graduallyaccumulates until it occupies the center of the fiber bundles, which are further surroundedby a thin sheath of micro fibrils. These are the elastic fibers, the most numerouscomponent of the elastic fiber system. Because they are rich in the protein elastin, theystretch easily in response to tension.
  8. 8. A. BUNDLES OF ELASTIC MICRO FIBRILS (OXYTALAN) IN ZONULE,B. DEVELOPING ELASTIC FIBER WITH CORDS OF AMORPHOUS ELECTRON-LUCENT ELASTINBEING LAID DOWN ON THE MICROFIBRILLAR TEMPLATE.C. LARGE MATURE ELASTIC FIBER (BRUCHS ELASTICA, TANGENTIAL CUT) AT SITE OF TWOBRANCHES (ARROWHEADS).D. PREDOMINANTLY MICROFIBRILLAR (ARROWS) ELASTIC FIBERS (ELAUNIN TYPE) INTRABECULUM.
  9. 9. The elastic fiber system, by using different proportions of micro fibrils andelastin, constitutes a family of fibers whose variable functional characteristics areadapted to local tissue requirements. A precursor of elastin is proelastin, a globular molecule (molecular mass70 kDa) produced by fibroblasts in connective tissue and by smooth muscle cellsin blood vessels. Proelastin polymerizes, producing elastin, the amorphousrubberlike glycoprotein that predominates in mature fibers. Elastin is resistant toboiling, acid and alkali extraction, and digestion by the usual proteases. It is easilyhydrolyzed by elastase( present in pancreatic juice, neutrophils and macrophages,also produced by many bacterias such as pseudomonas, clostridium histolyticumand flavobacterium elastolyticum). Even a few snakes, like rattle and viper. The amino acid composition of elastin resembles that of collagen,because both are rich in glycine and proline. Elastin contains two unusual aminoacids, desmosine and isodesmosine, formed by covalent reactions among fourlysine residues. These reactions effectively cross-link elastin and are thought toaccount for the rubberlike qualities of this protein, which forms fibers at least fivetimes more extensible than rubber
  10. 10. ELASTIN MOLECULES AREJOINED BY COVALENT BONDSTO GENERATE AN EXTENSIVECROSS-LINKED NETWORK.BECAUSE EACH ELASTINMOLECULE IN THE NETWORKCAN EXPAND AND CONTRACTLIKE A RANDOM COIL, THEENTIRE NETWORK CANSTRETCH AND RECOIL LIKE ARUBBER BAND.
  11. 11. PATHOLOGY OF ELASTINThe arteries need to be elastic, the skin needs to be elastic all soft tissues need some recoil. “ELASTIN IS THE ANSWER” It has received much attention because it changes with age. The resistance of elastin tochemical agents is remarkable. It persists in necrotic tissues even after all other structureshave disappeared. Elastin shares with the collagen the molecular feature of cross-linkage aswell as the cross linking enzyme lysyl oxidase and thus shares some pathology like collagen,namely disturbances induced by cross linking inhibitors such as those that occur in, LATHYRISMLathyrism or Neurolathyrism is a neurological disease ofhumans and domestic animals, caused by eating certain legumes of the genus Lathyrus, thataffects the linking of collagen) and copper deficiency(sensory ataxia{irregular coordinationdue to proprioceptive loss}, spasticity, muscle weakness, and more rarely visual loss dueperipheral neuropathy(damage in the peripheral nerves), myelopathy(disease of the spinalcord) and rarely optic neuropathy).
  12. 12. Compared with rubber threads, elastin can stretch at least 5 times more, but intissues they cant reach that limit, because they are intertwined with thickercollagen fibers. Water is required for its recoil, molecule contains hydrophobicregions, which maybe related to its tendency to bind lipids.Also bind fatty acids, and once it is thus complexed, it is more susceptible todigestion by elastase. These features may play a role in atherosclerotic plaques,where elastin and lipid abound.
  13. 13. GENETIC DEFECTS AFFECTING ELASTIC FIBERSMARFAN SYNDROME; Marfan syndrome is named after Antoine Marfan, theFrench pediatrician who first described the condition in 1896. People with Marfans tend tobe unusually tall, with long limbs and long, thin fingers. Marfan syndrome has a range ofexpressions, from mild to severe. The most serious complications are defects of the heartvalves and aorta. It may also affect the lungs, eyes, the Dural sac surrounding the spinalcord, skeleton and the hard palate.HISTOLOGY; of aortic wall shows a thickened wall with defective elastin and poolsof metachromatic material, after a great deal of work, the molecular defect was linked to 2fibrillin genes on chromosome 5 and 15 (67, 72, 82). Now the glycoprotein fibrillin is acomponent of the micro fibrils associated with elastin and since it is abundant in aorta,periosteum and ligaments, resulting in the tissues most affected by Marfans.MARFANS, IS RECOGNIZED AS A DISEASE OF ELASTIC FIBERS, WHICHDISTURB THESE FIBERS WITHOUT AFFECTING THE ELASTIN MOLECULEITSELF.
  14. 14. The media shows a slit (low power) which corresponds to the separation of the layersdue to mucoid degeneration of the connective tissue (seen at high power).There is focal loss of elastic and muscle fibers in the media.
  15. 15. MMP’S?
  16. 16. TRIVIAMatrix metalloproteinases (MMPs) are zinc-dependent endopeptidases;other family members are adamalysins, serralysins, and astacins. The MMPsbelong to a larger family of proteases known as the metzincin superfamily.Collectively, they are capable of degrading all kinds of extracellular matrixproteins.
  17. 17. CUTIS LAXA (ELASTOLYSIS)group of rare connective tissue disorders in which the skin becomes inelasticand hangs loosely in folds, in which elastic fibers are too few. The skin lacksRECOIL and appears too large for the body, face is typically droopy recallinga bloodhound, voice may be baritonal because vocal cords too lack tension.Our outward appearance depends a great deal on elastic.
  18. 18. PATHOPHYSIOLOGYIn most cases of cutis laxa, the biochemical and molecular basis of the skinchanges are unclear. However, the histopathologic analysis of the skin in severalpatients reveals alterations in the quantity or the morphology of elastin in whichfragmentation or a loss of elastic fibers is present. Additionally, evidence ofabnormal cross-linking of elastin exists in some patients with cutis laxa.Factors;a. Copper deficiency,b. Lysyl oxidase,c. Elastases,d. Elastase inhibitors,contribute to abnormal elastin degradation.
  19. 19. 1. Lysyl oxidase; a copper-dependent enzyme, is important in the synthesis andcross-linking of elastin and collagen. Therefore, low levels of serum copper couldlead to diminished elastin synthesis. However, only a few patients with cutis laxahave demonstrated low serum copper levels. Defective copper utilization may alsolead to decreased activity of elastase inhibitor alpha-1 antitrypsin, resulting indestruction of elastic fibers.2. Cultured dermal fibroblasts; from patients with cutis laxa have shown increasedelastolysis activity compared with healthy skin, and elastolysis has been suggestedto result from increased elastase activity.3. Inflammatory cells; or their mediators might damage elastic fibers. Polymorphnuclear leukocytes and macrophages release Elastases, which could damage elasticfibers with subsequent phagocytosis.4. Excessive loss of cutaneous elastin; in one patient with cutis laxa appeared to berelated to the combined effects of low lysyl oxidase activity with high levels ofcathepsin G, an elastolytic protease.Indeed, cutis laxa could result from mutations that affect the synthesis, thestabilization, or the degradation of elastic fibers.
  20. 20. C. SPARSE MIXED PERIVASCULARINFILTRATE (H/E STAIN)D. COMPLETE LOSS OF ELASTICFIBERS (ELASTIN STAIN)BOTH IN X20
  21. 21. ACQUIRED DEFECTS OF ELASTINElastin is particularly sensitive to aging, and elastogenesis in the skin isaffected by sunlight, a problem not shared by collagen. The organs richest inelastin are lungs, and the pathogenesis of emphysema is centered around thedestruction of elastic fibers.AGING; Cross linking increases with age in elastin as it does in collagen.,which means that the arteries become progressively stiffer. The amount ofcalcium bound to the elastic fibers also increases with age. This is attributed tothe increase in acidic amino acids(aspartate and glutamic) which could bindcalcium; but it may also depend on an intrinsic property of the elastinmolecule, which can nucleate apatite crystals. Like wise in someatherosclerotic arteries the internal elastic lamina is specifically and strikinglycalcified.
  22. 22. NORMAL VESSEL MORPHOLOGY
  23. 23. SOLAR ELASTOSIS (DERMATOHELIOSIS)Sun worshippers disease, Can affect everyones face after the age of 30.C/F; include finely wrinkled and losing elasticity at first, eventuallybecomes lumpy. Coarsely wrinkled and even criss crossed by deep furrows.Classic example is a “redneck”, which is also known as cutis rhomboidalisnuchae.MICROSCOPICALLY; All skin areas exposed to the sun, the dermis isthickened and contains seemingly amorphous pools of basophilic hyalin. Thismaterial takes up dyes that normally stain elastin fibers, hence the nameelastosis. It is believed that the dermal fibroblasts produce defective elasticfibers, because of damage by sun rays.
  24. 24. PATHOPHYSIOLOGYA much-cited hypothesis focuses on degradation of collagen fiber bykeratinocyte- and fibroblast-derived matrix metalloproteinases.HISTOPATHOLOGICALLY; Damage to elastic fibers appears to bemore important. The elastotic material observed in photo aged skin is stronglypositive for elastin, which is a major component of the elastic fiber and ishighly resistant to proteolysis. It would seem, therefore, that accumulation ofelastin is an important factor in the pathophysiology of photo aging, it mayinterfere structurally with repair of the elastic fiber and collagen fibernetworks.The accumulation of elastotic material and damage to elastic and collagenfibers result in a dysfunctional extracellular matrix and lead to loss of elasticityof the skin, wrinkle formation, and telangiectasia.
  25. 25. HISTOPATHOLOGY OF(A) NORMAL SKIN AND(B) PHOTO AGED SKIN. PHOTO AGED SKIN ,ISCHARACTERIZED BY ATYPICALKERATINOCYTES ANDIRREGULAR DISTRIBUTION OFMELANOCYTES (ARROWS) IN THEEPIDERMIS AND CONSPICUOUSFIBROUS AND AMORPHOUSBASOPHILIC MATERIAL (CROSSES)IN THE MID- AND UPPER-DERMIS, SO-CALLED SOLARELASTOSIS.
  26. 26. TYPICAL REDNECK
  27. 27. EMPYSEMARecall the structure of lung, which is divided ina. Myriads of microscopic air spaces(alveoli) purpose?Emphysema is chronic obstructive pulmonary disease (COPD). Emphysema isdefined pathologically as an abnormal permanent enlargement of air spacesdistal to the terminal bronchioles, accompanied by the destruction of alveolarwalls and without obvious fibrosis. Emphysema frequently occurs inassociation with chronic bronchitis.The 3 described morphological types of emphysema are centriacinar,panacinar, and paraseptal.
  28. 28. PATHOGENESISThe walls between the alveoli tend to break down, so that the air spacesbecomes larger and larger and the surface area is thus reduced considerably.The lung tissue gets robbed off of its elastin scaffolding, as a result of itsimbalance between elastase and anti elastase. NAME?Alpha -1 antitrypsin is powerless against macrophage elastase but veryeffective against granulocyte elastase. In smokers, more granulocytes areattracted into the lungs, Y ? And there they release their enzymes, elastaseincluded, either because they are activated or because they die.The enzyme cross the endothelial barrier (HOW ?), and the elastase attacksthe functionally critical elastin framework of the alveoli. The elastase now, offcourse is more effective if the level of the plasma inhibitor is low. The finalresult is a breakdown of the alveolar walls; EMPHYSEMA.
  29. 29. PROTEOGYLCANSGlycosaminoglycans (originally called acid mucopolysaccharides) arelinear polysaccharides formed by repeating disaccharide units usuallycomposed of a uronic acid and a hexosamine. The hexosamine can beglucosamine or galactosamine, and the uronic acid can be glucuronic oriduronic acid. With the exception of hyaluronic acid, these linear chains arebound covalently to a protein core forming a proteoglycan molecule.Proteoglycans can bind to a great number of cations(usually sodium) byelectrostatic (ionic) bonds. Proteoglycans are intensely hydrated structureswith a thick layer of solvation water surrounding the molecule. When fullyhydrated, proteoglycans fill a much larger volume (domain) than they do intheir anhydrous state and are highly viscous.MAIN FUCNTION IS CELL RECOGNITION, ATTACHMENT ANDGROWTH CONTROL.
  30. 30. PROTEOGLYCANS CONTAIN ACORE OF PROTEIN (VERTICALROD IN DRAWING) TO WHICHMOLECULES OFGLYCOSAMINOGLYCANS (GAGS)ARE COVALENTLY BOUND. ALSOKNOWN AS A TYPICAL TEST TUBEBRUSH
  31. 31. The proteoglycans are composed of a core protein associated with the four mainglycosaminoglycans: dermatan sulfate, chondroitin sulfate, keratan sulfate,and heparan sulfate.In cartilage, the proteoglycan molecules have been shown to be bound to ahyaluronic acid chain, forming larger molecules—proteoglycan aggregates. Theacidic groups of proteoglycans cause these molecules to bind to the basic aminoacid residues of collagen.Proteoglycans are distinguished by their molecular diversity and can be located incytoplasmic granules such as heparin of mast cells, in the cell surface, and in theextracellular matrix. One of the most important extracellular matrix proteoglycansis aggrecan, the dominant proteoglycan in cartilage.In the aggrecan, several molecules of proteoglycans (containing chondroitinsulfate chains) are noncovalently associated by its core protein to a molecule ofhyaluronic acid. Cell-surface proteoglycans are attached to the surface of manytypes of cells, particularly epithelial cells. Two examples are syndecan and fibroglycan.The core protein of cell-surface proteoglycans spans the plasma membrane andcontains a short cytosolic extension. A small number of heparan sulfate orchondroitin sulfate chains of glycosaminoglycans is attached to the extracellularextension of the core protein.
  32. 32. In addition to acting as structural components of the extracellular matrix andanchoring cells to the matrix, both extracellular and surface proteoglycans alsobind many protein growth factors (e.g., transforming growth factor, TGF-, offibroblasts).The synthesis of proteoglycans begins in the rough endoplasmic reticulumwith the synthesis of the protein moiety of the molecule. Glycosylation isinitiated in the rough endoplasmic reticulum and is completed in the Golgicomplex, where sulfation also occurs.
  33. 33. PATHOLOGY OF PROTEOGLYCANSOSTEOARTHRITIS (DEGENERATIVE ARTHRITIS); It represents aheterogeneous group of conditions that result in common histopathologicand radiologic changes. It is a degenerative disorder that results from thebiochemical breakdown of articular (hyaline) cartilage in the synovial joints.However, the current concept holds that osteoarthritis involves not just thearticular cartilage but the entire joint organ, including the subchondral boneand synovium.Osteoarthritis predominantly involves the weight-bearing joints, including theknees, hips, cervical and lumbosacral spine, and feet.
  34. 34. PATHOGENESISEven though osteoarthritis has always been classified as a noninflammatoryarthritis, increasing evidence has shown that inflammation occurs as cytokinesand metalloproteinases are released into the joint. Theses agents are involvedin the excessive matrix degradation that characterizes cartilage degeneration inosteoarthritis.In early osteoarthritis, swelling of the cartilage usually occurs, due to theincreased synthesis of proteoglycans; this reflects an effort by thechondrocytes to repair cartilage damage.As osteoarthritis progresses, however, the level of proteoglycans eventuallydrops very low, causing the cartilage to soften and lose elasticity, therebyfurther compromising joint surface integrity..
  35. 35. PRESSURE AREASGreater loss of joint space occurs at those areas subjected to the greatestpressures. Erosion of the damaged cartilage in an osteoarthritic jointprogresses until the underlying bone is exposed. Bone denuded of itsprotective cartilage continues to articulate with the opposing surface.Eventually, the increasing stresses exceed the biomechanical yield strength ofthe bone.The subchondral bone responds with vascular invasion and increasedcellularity, becoming thickened and dense (a process known as eburnation) atareas of pressure. The traumatized subchondral bone may also undergo cysticdegeneration, due to either osseous necrosis secondary to chronic impactionor to the intrusion of synovial fluid.
  36. 36. NON-PRESSURE AREASAt nonpressure areas along the articular margin, vascularization ofsubchondral marrow, osseous metaplasia of synovial connective tissue, andossifying cartilaginous protrusions lead to irregular outgrowth of new bone(osteophytes). Fragmentation of these osteophytes or of the articular cartilageitself results in the presence of intra-articular loose bodies (joint mice).
  37. 37. MEDIAL COMPARTMENT WITH FULL-THICKNESS ARTICULAR CARTILAGELOSS AT BOTH FEMORAL AND TIBIALASPECTS, EXPOSING THE PINKVASCULARIZED UNDERLYING BONE(ARROW). NOTE THE SLIGHTLYYELLOWISH WHITE APPEARANCE OFTHE NORMAL ADJACENT CARTILAGE(ASTERISK), AND THE NORMALCARTILAGE AT THE LATERALFEMORAL CONDYLE AND TROCHLEA.
  38. 38. THIS 3D GRAPHIC REPRESENTATIONDEMONSTRATES THE DENSELYPACKED LARGE PROTEOGLYCANAGGREGATES "TRAPPED" BETWEENTHE BUNDLES OF COLLAGEN, BOTHPRODUCED BY THE CHONDROCYTES.IN THE BACKGROUND NOTE THEORGANIZATION OF COLLAGENFIBERS, WITH AN OVERALL "UPSIDE-DOWN U" CONFIGURATION(BENNINGHOFFS ARCADES)LEADING TO PARALLEL FIBERSALONG THE MAIN ARTICULAR FORCEVECTOR AT THE DEEP REGIONS OFCARTILAGE, WHILE AT THE JOINTSURFACE THE FIBERS ARE PARALLELTO THE SURFACE. THISORGANIZATION IS THOUGHT TO BEREFLECTED IN THE MR SIGNAL FROMDIFFERENT REGIONS OF ARTICULAR CARTILAGE.
  39. 39. ARTICULAR CARTILAGE. THE LOSS OF PROTEOGLYCANS RESULTS IN DECREASED METACHROMASIA OF THE CARTILAGE.THIS ACCOUNTS FOR THE EOSINOPHILIC AS OPPOSED TO BASOPHILIC STAINING. THE SURFACE OF THE ARTICULARCARTILAGE SHOULD BE SMOOTH; IN THIS CASE FISSURING, PITTING AND FLAKING ARE CLEARLY SEEN. IN SOME AREASTHE ARTICULAR CARTILAGE HAS DISAPPEARED ALTOGETHER EXPOSING SUBCHONDRAL BONE. THIS EXPOSURE OFSUBCHONDRAL BONE MAY LEAD TO INCREASED VASCULARITY AND THICKENING OF THE BONY TRABECULAE . THESECHANGES ARE CLEARLY SEEN IN A NUMBER OF AREAS ON THIS SLIDE. IN OTHER AREAS DEATH OF OSTEOCYTES ORINCREASED OSTEOCLASTIC ACTIVITY HAS LED TO THINNING OF THE BONY TRABECULAE WITH MICROCYSTFORMATION. AS A RESULT OF ALL THESE CHANGES, DEFORMATION OF THE ARTICULAR ENDS OF THE BONE MAY OCCUR.
  40. 40. MYXEDEMA (MUCOUS EDEMA)The term myxedema has been applied to several clinical entities and is oftenused interchangeably with severe hypothyroidism, the common clinicalcondition in which the thyroid gland produces abnormally low levels ofhormones.Myxedema also refers to 2 different dermatologic conditions. Pretibialmyxedema, an uncommon skin disorder, occurs not in cases ofhypothyroidism but in hyperthyroid states, including, most commonly, Gravesdisease. The term pretibial is somewhat misleading, because the condition canaffect other areas of the body and could more accurately be called localizeddermopathy.The other skin condition, called myxedema, occurs in severe, long-standinghypothyroid states and is caused by the deposition of mucopolysaccharideswithin the dermis.
  41. 41. Myxedema coma/crisis occurs most commonly in older women with long-standing, undiagnosed or undertreated hypothyroidism who experience anadditional significant stress, such as infection, a systemic disease, certainmedications, and exposure to a cold environment.When hypothyroidism is long-standing, physiologic adaptations occur.Reduced metabolic rate and decreased oxygen consumption result inperipheral vasoconstriction, which maintains core temperature. The numberof beta-adrenergic receptors is reduced, usually with preservation of alpha-adrenergic receptors and circulating catecholamines, causing beta/alpha-adrenergic imbalance, diastolic hypertension, and reduced total blood volume.Myxedema coma/crisis is a form of decompensated hypothyroidism in whichadaptations are no longer sufficient. Essentially, all organ systems are affected
  42. 42. PATHOGENESISThe increased deposition of glycosaminoglycan is not fully understood, howevertwo mechanisms predominate.1. Exophthalmos in particular results from TSH receptor stimulation onfibroblasts behind the eyes which leads to increased glycosaminoglycan deposition.It is thought that many cells responsible for forming connective tissue react toincreases in TSH levels.2. Secondarily, in autoimmune thyroid diseases lymphocytes react to the TSHreceptor. Thus, in addition to the inflammation within the thyroid, any cell thatexpresses the TSH receptor will likely experience lymphocytic infiltrates as well.The inflammation can cause tissue damage and scar tissue formation, explainingthe deposition of glycosaminoglycans.The increased deposition of glycosaminoglycans causes an osmotic edema andfluid collection. Hashimotos thyroiditis is the most common cause of myxedemain the United States.
  43. 43. AT HIGHER POWER OFTHE SAME LESION,SPINDLED-TO-STELLATEFIBROBLASTS FLOATWITHIN THIS MYXOIDSTROMA. CYTOLOGICALATYPIA IS NOT NOTED.
  44. 44. MOHYMAN ET AL SPECIAL THANKS TO LIPTON YELLOW LABEL.

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