Miller-Cartilage and OA Flashcards
what are some physical properties of cartilage?
Viscoelastic: Properties vary according to rate of force application.
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Biphasic—property of liquid and solid
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Cartilage homeostasis disrupted by:
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Direct trauma/excess or inadequate forces
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Loss of underlying bone structure
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Genetic defects in normal structure/function
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Chemical/enzymatic threats
Review the differences between normal aging and osteoarthritis
Water
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Approximately 75% of cartilage
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Highest at surface or superficial layers
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Recurrent low-level forces shifts water in and out of extracellular matrix (ECM)
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Responsible for nutrition and lubrication
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H2O decreases with aging
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H2O increases in osteoarthritis
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
Review the organic components of cartilage
Type II collagen: 90%–95% of collagen
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Triple helix of α chains (derived from COL2A1 gene)
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Genetic defects of type II cause achondrogenesis (lethal at birth), spondyloepiphyseal dysplasia congenita, precocious arthritis
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Types IX and XI are “linking collagens”
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Type X found only near calcified cartilage, including:
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Calcified zone of articular cartilage’s tidemark
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Hypertrophic zone of the physis (genetic defect of type X leads to Schmid metaphyseal chondrodysplasia)
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Fracture callus and calcifying cartilaginous tumors
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Provides shear and tensile strength
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Contributes to viscoelastic behavior in that it restrains “swelling” of aggrecan
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Proteoglycans
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Make up approximately 10% of wet weight (30% of dry weight) (Fig. 1.28).
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Half-life of 3 months
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Provide compression strength
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Responsible for cartilage’s porous structure
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Trap and hold water
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Produced by chondrocytes
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Most common is aggrecan.
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Large macromolecules shaped like bristle brushes (see Fig. 1.28)
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Composed of repeating disaccharide subunits or glycosaminoglycans attached to protein core
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Repeating carboxyl and sulfate groups which are ionized in solution to COO−and SO3−
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Repel each other but attract positive cations
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Increase osmotic pressure, which traps and holds water and is responsible for ECM’s hydrophilic behavior
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Provides turgor of matrix
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Chondroitin sulfate (most prevalent glycosaminoglycan in cartilage)
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Chondroitin 4-sulfate decreases with age
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Chondroitin 6-sulfate remains constant
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Keratin sulfate
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Increases with age.
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Multiple core proteins in turn attached to hyaluronic acid (through link proteins) producing proteoglycan aggregate
Review chondrocytes
1%–5% of wet weight
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Only cells in cartilage
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Derived from undifferentiated mesenchymal precursors
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BMP-2 and the transcriptional factor SOX-9 important in regulating chondrocyte differentiation and formation
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Mechanotransduction—metabolism modulated via mechanical stimulation
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Cyclical loads of walking stimulate chondrocytes to form matrix
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Low loads (1–5 MPa) at moderate frequency (≈1 Hz)
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Primary cilia are the mechanosensory organ “antennae” for cells.
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Produce the extracellular matrix of collagen and proteoglycans
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Intracellular synthesis of procollagen, link peptide, hyaluronic acid, proteoglycans
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Extracellular assembly of component parts
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Produce proteins and enzymes and maintain matrix
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IL-1β (also from synovium and WBCs): main cartilage destroyer
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Metalloproteinases—break down cartilage matrix
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Collagenase—dissolves collagen (matrix metalloproteinase 13 [MMP-13])
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Aggrecanase—degrades proteoglycans (extracellular protease enzyme ADAMT)
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Enzyme inhibitors—protect cartilage
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Tissue inhibitors of metalloproteinases (TIMPs)
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Plasminogen activator inhibitor-1 (PAI-1)
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Chondrocytes are most dense and most active in the superficial zone.
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Deeper cartilage zone chondrocytes less metabolically active
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Decreased rough endoplasmic reticulum
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Increased intraplasmic filaments (degenerative products)
Review cartilage layers
Zone 1: superficial or tangential zone (10%–20% of thickness)
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Thin lamina splendens
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Flat chondrocytes
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Collagen fibers
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Highest concentration
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Parallel to joint surface strength against shear
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Greatest tensile stiffness
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Lowest concentration of proteoglycans
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Highest concentration of water
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Zone 2: middle or transition zone (40%–60% of thickness)
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Collagen fibers more random and less dense
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High levels of water and proteoglycan
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Zone 3: deep zone (30% of thickness)
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Lower water content
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Highest concentration of proteoglycan
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Chondrocytes and collagen fibers arranged perpendicular to articular surface
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Zone 4: calcified cartilage zone
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Begins at tidemark
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Transitions stiffness from flexible cartilage to rigid subchondral bone
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Low concentration of proteoglycans
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Type X collagen found here
what is lubricin?
Lubricin
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Mucinous glycoprotein that binds to hyaluronic acid
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Also present in lamina splendens
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Contributes to boundary lubrication
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Lubricant is present between two surfaces but its thickness is inadequate to prevent contact throughout the surfaces
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Defect associated with camptodactyly-arthropathy–coxa vara–pericarditis (CACP) syndrome
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Elastohydrodynamic lubrication
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Major mode of lubrication in joints
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Lubricant pressure causes elastic deformation of the opposing surfaces.
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This elastic deformation increases conformity.
what are cartilage changes with arthritis?
Increase in cells early (cloning)
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Loss of smooth lamina leads to fibrillation/fissures.
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Higher coefficient of friction
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Chondrocytes react to IL-1β and TNF and produce nitric oxide
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IL-1 stimulates MMPs, which degrade matrix.
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Collagenases (MMP-13)—first irreversible step
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Aggrecanase—degrade proteoglycans (ADAMTs)
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Stromelysin
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Decreased size and content of proteoglycan molecules
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Decreased keratan SO4− and increased chondroitin/keratan ratio
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Increase in percentage of nonaggregated glycosaminoglycans
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Higher water content and greater permeability initially followed by lower water content in later stages
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Decreased modulus of elasticity (less stiff) and tensile strength
what are cartilage changes with aging?
Decreased number of chondrocytes (but larger in size)
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Increased lysosomal enzymes
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Senescence markers of chondrocytes include telomere erosion, higher β-galactosidase expression, and reduced Wnt2 expression
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Lower response to growth factors (TGF-β)
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Decreased matrix production and matrix maintenance
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Decreased chondroitin SO4− (but increased keratan SO4−)
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Proteoglycan molecules smaller, so less able to hold water (lower water content)
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Increase in advanced glycosylation end products
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Yellows and stiffens cartilage
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Greater stiffness or modulus of elasticity but less tensile strength
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Increased decorin—decorates collagen for cross-links
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Increased collagen cross-links and diameter
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“Dried up old cartilage is yellow, weak, brittle, & stiff”
review growth factors and cartilage injury
IL-1 stimulates MMP, COX-2, and nitric oxide synthetase, which degrades cartilage.
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TGF-β stimulates synthesis of ECM and decreases activity of IL-1 and MMP’s
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Also stimulates chondrogenesis in vitro
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BMP-2, BMP-7, and IGF-1 also stimulate ECM production
what is elastrohydrodynamic lubrication?
Elastohydrodynamic lubrication
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Major mode of lubrication in joints
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Lubricant pressure causes elastic deformation of the opposing surfaces.
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This elastic deformation increases conformity.
review the IL-1 cascade for cartilage degredation:
review the DMARDs for Rheumatoid:
Biologic DMARDs
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Target TNF-α: etanercept, infliximab, adalimumab
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Targets IL-1: anakinra
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Targets CD20: rituximab
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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).
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Risks of opportunistic infection and lymphoma
Intended to address underlying autoimmune response
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Conventional DMARDs take 2–6 months to work
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Methotrexate: folate analogue
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Inhibits purine metabolism and T-cell activation
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Inhibits neovascularization
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Adverse reactions (ADRs): toxic to bone marrow, liver, and lung
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Usually can continue through surgery
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Azathioprine: immunosuppressive agent
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ADR: neutropenia
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Cyclosporine: immunosuppressive agent
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Inhibits activation of CD4+ T cells
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ADRs: nephrotoxicity, neurotoxicity, gingival hyperplasia
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Hydroxychloroquine (Plaquenil)
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Inhibits toll-like receptor 9 (TLR9)
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ADR: retinal toxicity (requires ophthalmology follow-up)
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Usually can continue through surgery
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Sulfasalazine
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Decreases synthesis of inflammatory mediators
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ADRs: granulocytopenia, hemolytic anemia (glucose-6-phosphate dehydrogenase [G6PD])
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Usually can continue through surgery
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Minocycline
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Inhibits MMP collagenase
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ADR: cutaneous hyperpigmentation
How do osteophytes form?
Osteophyte formation due to pathologic activation of endochondral ossification by periarticular chondrocytes through Indian hedgehog (Ihh) mechanism
Review Rheumatoid arthritis
Most common inflammatory arthritis
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Affects 0.5%–1% of population; three times more common in women
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15% concordance rate in monozygotic twins
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Clinical presentation (see Fig. 1.32)
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Insidious subacute onset over 6 weeks
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Fatigue, malaise, anemia
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Morning stiffness and polyarthritis with swelling
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Hand and foot deformities are most common and are discussed in respective subsequent chapters
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Also common in the knees, elbows, shoulders, ankles, and cervical spine
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Subcutaneous rheumatoid nodules (Fig. 1.34)
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Juxtaarticular erosions and periarticular osteopenia on radiographs
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2010 American College of Rheumatology Classification Criteria for RA are summarized in Table 1.21.
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Diagnosis requires score 6 or more
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Criteria include
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Number of joints involved and duration of involvement
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Positive laboratory test results often found
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Erythrocyte sedimentation rate (ESR), C-reactive protein (CRP)
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Rheumatoid factor (RF) titer
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Antibody (immunoglobulin [Ig] M) against the Fc (crystallizable fragment) portion of IgG
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Positive result in about 80%
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Test for anticyclic citrullinated protein (anti-CCP) antibodies
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Also known as anti-CCP antibodies (ACPAs)
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Most sensitive and specific test (≈90% specific)
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Presence linked to more aggressive disease
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Pathogenesis
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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)
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Mononuclear cells are primary mediator of RA tissue damage
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Initial response in soft tissues—neovascularization and synovitis
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CD4+ T lymphocytes (helper cells) activate synovial cells through direct cell-cell contact
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Synoviocytes produce cytokines
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Macrophages (type A): main source for TNF-α, IL-1
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Fibroblast (type B): main source for MMPs, proteases, and RANKL
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B lymphocytes (plasma cells): make RF, anti-CCP antibodies
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TNF-α, IL-1, IL-6, IL-7 upregulated
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IL-1: Regulator of inflammation and matrix destruction
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TNF-α:
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Upregulates endothelial adhesion molecules and stimulates angiogenesis
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Promotes influx of leukocytes and activates synovial fibroblasts
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Promotes pain receptor pathways
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Drives osteoclastogenesis
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Later response
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Synovial cells invade cartilage “pannus” and release MMPs, causing chondrolysis
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Periarticular bone erosions
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Cytokines stimulate osteoblasts and synovial B cells to make RANKL, which joins with RANK to activate osteoclasts. Responsible for bone destruction.
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Osteoclasts secrete cathepsin K and carbonic anhydrase.
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Systemic manifestations
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Rheumatoid vasculitis
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Distal splinter hemorrhage
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Cutaneous ulcers (pyoderma gangrenosum)
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Visceral arteritis
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Pericarditis and pericardial effusion
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Pulmonary disease including nodules and fibrosis
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Felty syndrome: severe erosive RA with splenomegaly and leukopenia
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Treatments and their perioperative considerations
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Regimen variable and often employs multiple agents
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NSAIDs: help symptoms early—antiinflammatory effects
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Should be held for 7–10 days preoperatively.
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Low-dose steroids
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Decrease prostaglandins and leukotrienes
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Used initially as “bridge therapy” to disease-modifying antirheumatic drugs (DMARDs)
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“Stress dose” steroid should be used perioperatively for patients on long-term steroid therapy
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.
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).
