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Flashcards in Miller-Cartilage and OA Deck (19)
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1

what are some physical properties of cartilage?

Viscoelastic: Properties vary according to rate of force application.

Biphasic—property of liquid and solid

Cartilage homeostasis disrupted by:

Direct trauma/excess or inadequate forces

Loss of underlying bone structure

Genetic defects in normal structure/function

Chemical/enzymatic threats

2

Review the differences between normal aging and osteoarthritis

Water

Approximately 75% of cartilage

Highest at surface or superficial layers

Recurrent low-level forces shifts water in and out of extracellular matrix (ECM)

Responsible for nutrition and lubrication

H2O decreases with aging

H2O increases in osteoarthritis

3

Review Genetic diseases associated with collagen

TYPE 1- Osteogenesis imperfecta

TYPE1, 3, 5: Ehlers Danlos

TYPE II: Knist, AChondrogenesis, Precocious arthritis, Stickler, SED Congenita

TYPE 9- MED

TYPE 10, Schmids

4

Review the organic components of cartilage

Type II collagen: 90%–95% of collagen

Triple helix of α chains (derived from COL2A1 gene)

Genetic defects of type II cause achondrogenesis (lethal at birth), spondyloepiphyseal dysplasia congenita, precocious arthritis

Types IX and XI are “linking collagens”

Type X found only near calcified cartilage, including:

Calcified zone of articular cartilage’s tidemark

Hypertrophic zone of the physis (genetic defect of type X leads to Schmid metaphyseal chondrodysplasia)

Fracture callus and calcifying cartilaginous tumors

Provides shear and tensile strength

Contributes to viscoelastic behavior in that it restrains “swelling” of aggrecan

Proteoglycans

Make up approximately 10% of wet weight (30% of dry weight) (Fig. 1.28).

Half-life of 3 months

Provide compression strength

Responsible for cartilage’s porous structure

Trap and hold water

Produced by chondrocytes

Most common is aggrecan.

Large macromolecules shaped like bristle brushes (see Fig. 1.28)

Composed of repeating disaccharide subunits or glycosaminoglycans attached to protein core

Repeating carboxyl and sulfate groups which are ionized in solution to COO−and SO3−

Repel each other but attract positive cations

Increase osmotic pressure, which traps and holds water and is responsible for ECM’s hydrophilic behavior

Provides turgor of matrix

Chondroitin sulfate (most prevalent glycosaminoglycan in cartilage)

Chondroitin 4-sulfate decreases with age

Chondroitin 6-sulfate remains constant

Keratin sulfate

Increases with age.

Multiple core proteins in turn attached to hyaluronic acid (through link proteins) producing proteoglycan aggregate

5

Review chondrocytes

1%–5% of wet weight

Only cells in cartilage

Derived from undifferentiated mesenchymal precursors

BMP-2 and the transcriptional factor SOX-9 important in regulating chondrocyte differentiation and formation

Mechanotransduction—metabolism modulated via mechanical stimulation

Cyclical loads of walking stimulate chondrocytes to form matrix

Low loads (1–5 MPa) at moderate frequency (≈1 Hz)

Primary cilia are the mechanosensory organ “antennae” for cells.

Produce the extracellular matrix of collagen and proteoglycans

Intracellular synthesis of procollagen, link peptide, hyaluronic acid, proteoglycans

Extracellular assembly of component parts

Produce proteins and enzymes and maintain matrix

IL-1β (also from synovium and WBCs): main cartilage destroyer

Metalloproteinases—break down cartilage matrix

Collagenase—dissolves collagen (matrix metalloproteinase 13 [MMP-13])

Aggrecanase—degrades proteoglycans (extracellular protease enzyme ADAMT)

Enzyme inhibitors—protect cartilage

Tissue inhibitors of metalloproteinases (TIMPs)

Plasminogen activator inhibitor-1 (PAI-1)

Chondrocytes are most dense and most active in the superficial zone.

Deeper cartilage zone chondrocytes less metabolically active

Decreased rough endoplasmic reticulum

Increased intraplasmic filaments (degenerative products)

6

Review cartilage layers

Zone 1: superficial or tangential zone (10%–20% of thickness)

Thin lamina splendens

Flat chondrocytes

Collagen fibers

Highest concentration

Parallel to joint surface strength against shear

Greatest tensile stiffness

Lowest concentration of proteoglycans

Highest concentration of water

Zone 2: middle or transition zone (40%–60% of thickness)

Collagen fibers more random and less dense

High levels of water and proteoglycan

Zone 3: deep zone (30% of thickness)

Lower water content

Highest concentration of proteoglycan

Chondrocytes and collagen fibers arranged perpendicular to articular surface

Zone 4: calcified cartilage zone

Begins at tidemark

Transitions stiffness from flexible cartilage to rigid subchondral bone

Low concentration of proteoglycans

Type X collagen found here

7

what is lubricin?

Lubricin

Mucinous glycoprotein that binds to hyaluronic acid

Also present in lamina splendens

Contributes to boundary lubrication

Lubricant is present between two surfaces but its thickness is inadequate to prevent contact throughout the surfaces

Defect associated with camptodactyly-arthropathy–coxa vara–pericarditis (CACP) syndrome

Elastohydrodynamic lubrication

Major mode of lubrication in joints

Lubricant pressure causes elastic deformation of the opposing surfaces.

This elastic deformation increases conformity.

8

what are cartilage changes with arthritis?

Increase in cells early (cloning)

Loss of smooth lamina leads to fibrillation/fissures.

Higher coefficient of friction

Chondrocytes react to IL-1β and TNF and produce nitric oxide

IL-1 stimulates MMPs, which degrade matrix.

Collagenases (MMP-13)—first irreversible step

Aggrecanase—degrade proteoglycans (ADAMTs)

Stromelysin

Decreased size and content of proteoglycan molecules

Decreased keratan SO4− and increased chondroitin/keratan ratio

Increase in percentage of nonaggregated glycosaminoglycans

Higher water content and greater permeability initially followed by lower water content in later stages

Decreased modulus of elasticity (less stiff) and tensile strength

9

what are cartilage changes with aging?

Decreased number of chondrocytes (but larger in size)

Increased lysosomal enzymes

Senescence markers of chondrocytes include telomere erosion, higher β-galactosidase expression, and reduced Wnt2 expression

Lower response to growth factors (TGF-β)

Decreased matrix production and matrix maintenance

Decreased chondroitin SO4− (but increased keratan SO4−)

Proteoglycan molecules smaller, so less able to hold water (lower water content)

Increase in advanced glycosylation end products

Yellows and stiffens cartilage

Greater stiffness or modulus of elasticity but less tensile strength

Increased decorin—decorates collagen for cross-links

Increased collagen cross-links and diameter

“Dried up old cartilage is yellow, weak, brittle, & stiff”

10

review growth factors and cartilage injury

IL-1 stimulates MMP, COX-2, and nitric oxide synthetase, which degrades cartilage.

TGF-β stimulates synthesis of ECM and decreases activity of IL-1 and MMP’s

Also stimulates chondrogenesis in vitro

BMP-2, BMP-7, and IGF-1 also stimulate ECM production

11

what is elastrohydrodynamic lubrication?

Elastohydrodynamic lubrication

Major mode of lubrication in joints

Lubricant pressure causes elastic deformation of the opposing surfaces.

This elastic deformation increases conformity.

12

review the IL-1 cascade for cartilage degredation:

13

review the DMARDs for Rheumatoid:

Biologic DMARDs

Target TNF-α: etanercept, infliximab, adalimumab

Targets IL-1: anakinra

Targets CD20: rituximab

Surgery should be scheduled at end of dosing cycle (e.g., in a patient taking etanercept schedule, surgery should occur the second week after the first withheld dose).

Risks of opportunistic infection and lymphoma

 

Intended to address underlying autoimmune response

Conventional DMARDs take 2–6 months to work

Methotrexate: folate analogue

Inhibits purine metabolism and T-cell activation

Inhibits neovascularization

Adverse reactions (ADRs): toxic to bone marrow, liver, and lung

Usually can continue through surgery

Azathioprine: immunosuppressive agent

ADR: neutropenia

Cyclosporine: immunosuppressive agent

Inhibits activation of CD4+ T cells

ADRs: nephrotoxicity, neurotoxicity, gingival hyperplasia

Hydroxychloroquine (Plaquenil)

Inhibits toll-like receptor 9 (TLR9)

ADR: retinal toxicity (requires ophthalmology follow-up)

Usually can continue through surgery

Sulfasalazine

Decreases synthesis of inflammatory mediators

ADRs: granulocytopenia, hemolytic anemia (glucose-6-phosphate dehydrogenase [G6PD])

Usually can continue through surgery

Minocycline

Inhibits MMP collagenase

ADR: cutaneous hyperpigmentation

14

How do osteophytes form?

Osteophyte formation due to pathologic activation of endochondral ossification by periarticular chondrocytes through Indian hedgehog (Ihh) mechanism

15

Review Rheumatoid arthritis

Most common inflammatory arthritis

Affects 0.5%–1% of population; three times more common in women

15% concordance rate in monozygotic twins

Clinical presentation (see Fig. 1.32)

Insidious subacute onset over 6 weeks

Fatigue, malaise, anemia

Morning stiffness and polyarthritis with swelling

Hand and foot deformities are most common and are discussed in respective subsequent chapters

Also common in the knees, elbows, shoulders, ankles, and cervical spine

Subcutaneous rheumatoid nodules (Fig. 1.34)

Juxtaarticular erosions and periarticular osteopenia on radiographs

2010 American College of Rheumatology Classification Criteria for RA are summarized in Table 1.21.

Diagnosis requires score 6 or more

Criteria include

Number of joints involved and duration of involvement

Positive laboratory test results often found

Erythrocyte sedimentation rate (ESR), C-reactive protein (CRP)

Rheumatoid factor (RF) titer

Antibody (immunoglobulin [Ig] M) against the Fc (crystallizable fragment) portion of IgG

Positive result in about 80%

Test for anticyclic citrullinated protein (anti-CCP) antibodies

Also known as anti-CCP antibodies (ACPAs)

Most sensitive and specific test (≈90% specific)

Presence linked to more aggressive disease

Pathogenesis

T cell–mediated immune response from an infectious or environmental antigen (smoking is one known trigger) in a genetically susceptible individual (HLA-DR4 and HLA-DW4)

Mononuclear cells are primary mediator of RA tissue damage

Initial response in soft tissues—neovascularization and synovitis

CD4+ T lymphocytes (helper cells) activate synovial cells through direct cell-cell contact

Synoviocytes produce cytokines

Macrophages (type A): main source for TNF-α, IL-1

Fibroblast (type B): main source for MMPs, proteases, and RANKL

B lymphocytes (plasma cells): make RF, anti-CCP antibodies

TNF-α, IL-1, IL-6, IL-7 upregulated

IL-1: Regulator of inflammation and matrix destruction

TNF-α:

Upregulates endothelial adhesion molecules and stimulates angiogenesis

Promotes influx of leukocytes and activates synovial fibroblasts

Promotes pain receptor pathways

Drives osteoclastogenesis

Later response

Synovial cells invade cartilage “pannus” and release MMPs, causing chondrolysis

Periarticular bone erosions

Cytokines stimulate osteoblasts and synovial B cells to make RANKL, which joins with RANK to activate osteoclasts. Responsible for bone destruction.

Osteoclasts secrete cathepsin K and carbonic anhydrase.

Systemic manifestations

Rheumatoid vasculitis

Distal splinter hemorrhage

Cutaneous ulcers (pyoderma gangrenosum)

Visceral arteritis

Pericarditis and pericardial effusion

Pulmonary disease including nodules and fibrosis

Felty syndrome: severe erosive RA with splenomegaly and leukopenia

Treatments and their perioperative considerations

Regimen variable and often employs multiple agents

NSAIDs: help symptoms early—antiinflammatory effects

Should be held for 7–10 days preoperatively.

Low-dose steroids

Decrease prostaglandins and leukotrienes

Used initially as “bridge therapy” to disease-modifying antirheumatic drugs (DMARDs)

“Stress dose” steroid should be used perioperatively for patients on long-term steroid therapy

16

Review Lupus

Chronic inflammatory disease of unknown origin

90% of cases in women (blacks > whites)

Initially mediated by tissue-binding autoantibodies and immune complexes (type III hypersensitivity)

Pathophysiology

Susceptible genetics stimulated by environment

Immune system autoregulatory failure

Sustained production of antibody to self-antigens

Antinuclear antibodies (ANAs)—best screen; positive in 95%

Anti-dsDNA, anti-Sm, anti-La (SS-B), antihistone antibodies—drug-induced lupus

Immune complexes accumulate in various tissues and cause chronic inflammation

Skin/joints—rash and arthritis

Heart/kidney—pericarditis/nephritis

Blood vessels—vasculitis

Clinical findings

Bone and joint involvement—most common feature

Nonerosive polyarthritis affects over 75% (hand and wrist most common).

Osteonecrosis (especially with steroids)

Butterfly malar rash—classic feature

Fever, pancytopenia

Pharmacologic treatment similar to that for RA.

Seronegative spondyloarthropathies

Characterized by negative RF titer result and, often, positive HLA-B27 test result

Symptoms

Inflammatory back pain

Peripheral arthritis

Enthesitis—heel pain

Dactylitis—sausage digit

Eye—uveitis (iritis), conjunctivitis

Skin, mucosal, GI, urethral

Similar treatment routines, including NSAIDs, steroids, and DMARDs

17

Review lupus 2

Systemic lupus erythematosus. (A) Autoantibodies to DNA and DNA-binding proteins form immune complexes that stimulate immune system–directed inflammation throughout the body (type III hypersensitivity reaction). (B) Direct immunofluorescence with anti–immunoglobulin G antibodies shows immune complex deposits at two different places: a bandlike deposit along the epidermal basement membrane—positive result of lupus band test—and within the nuclei of the epidermal cells (ANAs). (C) Most patients have skin and joint involvement. The classic butterfly rash of SLE occurs in 10%–50% of patients with acute SLE. (D) The same immune complexes are seen in the basement membrane of the renal glomerulus. (E) Flea-bitten appearance of kidney specimen, with lupus nephritis causing various degrees of proteinuria, hematuria, and cellular casts.

18

Gout vs Pseudogout

Pathology from accumulation of crystal formation or deposition in or around joints

Gout: monosodium urate

CPDD, also called pseudogout: calcium pyrophosphate

Tumoral calcinosis: calcium apatite

Calcium oxalate

Gout (see Table 1.20)

Disorder of purine nucleic acid metabolism, causing hyperuricemia

Deposition of monosodium urate crystals in joints

Crystals activate inflammatory mediators

Inflammatory mediators are inhibited by colchicine.

Attacks precipitated by dehydration, excess alcohol or dietary purines, chemotherapy

Diagnosis

Recurrent acute joint pain

Men aged 40–60 years, postmenopausal women

Usually lower extremity, great toe (podagra)

Crystal deposition as tophi when chronic

Ear helix, eyelid, olecranon, Achilles tendon

Renal disease or stones—second most common site

Radiographic findings

Soft tissue swelling early: edema, tophi

Punched-out or rat bite periarticular erosions

Sclerotic overhanging borders

Synovial fluid findings

Concomitant septic arthritis must be ruled out

WBC count: wide range (5,000–80,000 cells/μL; average, 15,000–20,000 cells/μL), mostly PMNs

Yellow, needle-shaped crystals when parallel to compensator (Fig. 1.38A)

Strong negative birefringence

Treatment:

NSAIDs and colchicine (microtubule inhibitor that inhibits mitosis) for acute attack

Chronic/maintenance therapy

Weight loss, low-purine diet, limit of alcohol intake

Probenecid: uricosuric agent

Allopurinol: xanthine oxidase inhibitor

Febuxostat in renally impaired patients

Pseudogout (see Table 1.20)

Deposition of calcium pyrophosphate dehydrate (CPPD) crystals in joints

Associated with lupus, renal dialysis, hemochromatosis, hyperparathyroidism, RA, Wilson disease

Chondrocalcinosis

Calcification within hyaline or fibrocartilage or menisci

Seen in pseudogout but also in other conditions

Genetic version: ANKH gene mutation

Increases extracellular pyrophosphate

Synovial fluid findings

WBC counts 5000–100,000 cells/μL (average, 24,000 cells/μL)

Rhomboid-shaped crystals in WBCs

Weakly positively (blue) birefringent when parallel (see Fig. 1.38B)

Radiographic findings: fine linear calcification in hyaline cartilage and more diffuse calcification of menisci and other fibrocartilage (triangular fibrocartilage complex, acetabular labrum)

Treatment with NSAIDs and, potentially, steroid injection

Calcium hydroxyapatite crystal deposition disease

Apatite is primary crystal of normal bone.

Accumulates abnormally in areas of tissue damage or in hypercalcemic or hyperparathyroid states (chronic kidney disease [CKD])

Associated with

Acute attacks of bursitis/synovitis

Severe degenerative joint disease

Calcific tendinitis of rotator cuff and hip abductors

Destructive arthropathy can occur in the knee and shoulder.

Milwaukee shoulder: calcium phosphate deposition with cuff tear arthropathy

Calcium oxalate deposition

Primary oxalosis—rare genetic defect of liver enzymes

Alanine glyoxylate aminotransferase (AGT)

Glyoxylate reductase (GR)

Nephrocalcinosis, renal failure, and death by age 20 years

Treatment: liver/kidney transplantation

Secondary oxalosis—more common

Metabolic abnormalities of chronic renal insufficiency

Associated with calcium oxalate arthritis/periarthritis and nephrolithiasis

Diagnosis: synovial fluid usually contains fewer than 2000 WBCs/μL.

Birefringent bipyramidal crystals

19

Review hemophilic arthropathy

x-linked recessive defect of factor 8 or 9. 

 

 

 

Hemophilic arthropathy. (A) Recurrent knee effusions and synovitis. (B) Radiograph of end-stage arthropathy. (C) Synovial proliferation of hemophilic arthropathy demonstrates phagocytic (type A) synovial cells laden with iron pigment but no giant cells, polymorphonuclear leukocytes, and rare lymphocytes. (D) Bloody ankle effusion presentation of teen whose grandfather had a history of bleeding disorder. (E) End-stage hemophilic arthropathy of ankle demonstrates flattening of the talus (arrow).