Articular Cartilage - Basic Science

Introduction

Articular cartilage is one of five forms of cartilage
- hyaline or articular cartilage
- fibroelastic cartilage (meniscus)
- fibrocartilage (at tendon and ligament insertion into bone)
- elastic cartilage (trachea)
- physeal cartilage (growth plate)

Articular (hyaline) Cartilage Components

Function
- decreases friction and distributes loads
- cartilage exhibits stress-shielding of the solid matrix components due to its high water content, the incompressibility of water, and the structural organization of the proteoglycan and collagen molecules
Composition
- includes
  - extracellular matrix (water, 90% type II collagen, proteoglycans)
  - cells (chondrocytes)
- % by weight
  - water > collagen > proteoglycan > noncollagenous protein > cells
Extracellular matrix
- water
  - makes up 65% to 80% of mass of the cartilage
    - accounts for 80% of the weight near the surface
    - 65% at the deep zone
  - water content
    - decreases with normal aging
    - increases with osteoarthritis
      - increased water content leads to
        
        increased permeability
        
        decreased strength
        
        decreased Young Modulus of elasticity
- collagen
  - makes up 10 to 20% of total cartilage mass
  - type II collagen accounting for 90% to 95% of the total collagen content.
    - functions to provide cartilagenous framework and tensile strength
  - small amounts of types V, VI, IX, X, and XI collagen are also present
- proteoglycans
  - make up 10 to 15% of cartilage
  - function to provide compressive strength and attract water
  - aggrecan is most responsible for hydrophilic behavior
  - produced by chondrocytes
  - proteoglycans composed of GAG subunits
    - chondroitin sulfate
    - keratin sulfate
- noncollagenous protein
Cells
- chondrocytes
  - produce collagen, proteoglycans, and enzymes
  - derive from chondroblasts that are trapped in lacunae and become chondrocytes
  - chondrocyte metabolism responds to both mechanical (mechanical load, hydrostatic pressure change) and chemical stimuli (growth factors, cytokines)
  - immature articular cartilage has stem cells (mature articular cartilage does not)

Layers of Articular Cartilage

Normal articular cartilage is composed of three zones and the tidemark
- zones based on the shape of the chondrocytes and the orientation of the type II collagen.

Zones of Articular Cartilage
Superficial zone (tangential zone)	• Type II collagen orientation is parallel to joint • Has flattened chondrocytes, condensed collagen fibers, and sparse proteoglycans • Has the highest concentration of collagen and lowest concentration of proteoglycans • only zone where articular cartilage progenitor cells have been found
Intermediate zone	• Type II collagen has an oblique or random organization • Is the thickest layer with round chondrocytes, and abundant proteoglycan content
Deep layer (basal layer)	• Type II collagen is perpendicular to joint and crosses tidemark; has the highest concentration of proteoglycans • Round chondrocytes arranged in columns
Tidemark	• Is deep to the basal layer and separates the true articular cartilage from the deeper cartilage that is a remnant of the cartilage anlage, which participated in endochondral ossification during longitudinal growth in childhood. • The tidemark divides - the superficial, uncalcified cartilage from the deeper, calcified cartilage - division between nutritional sources for the chondrocytes • The tidemark is found only in joints • Most prominently in the adult and nongrowing joint
Subchondral Bone

Growth Factors

PDGF
- thought to be involved with healing of articular cartilage lacerations
- effects extrapolated from PRP (which contains it)
- no adverse effects in normal joints
TGF-B
- stimulates proteoglycan and ECM synthesis
- decreases catabolic activity of IL-1 and MMPs
- causes synovial proliferation and fibrosis
- induces osteophyte formation
b-FGF (Basic Fibroblastic Growth Factor)
- stimulates DNA synthesis in articular chondrocytes
IGF-1 (Insulin growth factor -1)
- stimulates DNA and cartilage matrix synthesis in adult articular cartilage
- stimulates ECM synthesis
- decreaes synovial thickening and chronic synovial inflammation
- additive when combined with TGF-b

Nourishment and Metabolism

Cartilage is avascular
Nourished by
- synovial fluid at the surface
- subchondral bone at the base
Relies on glycolysis for ATP production

Mechanical Stress Response

Physiologic stress stimulates matrix synthesis and inhibits chondrolysis
- cyclic stress (1-5 MPa)
- moderate frequency (0.1-1 Hz)
- low rates (<1000 MPa/s)
Excess stress suppresses matrix synthesis and promotes chondrolysis
- excess stress (>5 MPa)
- static load (<0.01 Hz)
- high rates (>1000 MPa/s)
Cellular responses
- primary cilia act as a mechanosensory organ on chondrocytes and osteoblasts
- transduction of mechanical signals involves integrins
Repetitive loading
- moderate running increases cartilage thickness and proteoglycan content
- strenuous loading leads to cartilage thinning and proteoglycan loss
- immobilization leads to cartilage thinning, softening and proteoglycan loss

Wear Mechanics

Forms of lubrication
- elastohydrodynamic
  - main mechanism during dynamic joint function
  - elastic deformation of articular surfaces
  - thin films of lubricant separate the surfaces
  - a fully congruent joint will not allow a fluid film to form
- boundary (slippery surfaces)
  - bearing surface is non-deformable
  - lubricant only partially separates surfaces
  - superficial zone proteins have a role in this lubrication mechanism
- boosted (fluid entrapment)
  - concentration of lubricating fluid in pools
  - trapped by regions of bearing surfaces that are making contact
- hydrodynamic
  - fluid separates surfaces when one surface is sliding on the other
- weeping
  - fluid shifts out of articular cartilage in response to load
  - surfaces separated by hydrostatic pressure
Mechanisms of wear
- adhesion
- abrasion
- transfer
- fatigue
- third body

Aging in Articular Cartilage

With age changes in articular cartilage include
- increases in
  - chondrocytes size
  - protein content
  - stiffness (passive glycation leads to increased stiffness of collagen)
  - increase in ratio of proteoglycan keratin sulfate to chondroitin sulfate
- decrease in
  - absolute number of cells (becomes hypocellular, despite the fact that individual chondrocytes are increasing in size)
  - water content (differentiates from osteoarthritis where water content actually increases)
  - solubility
  - proteoglycan size
  - elasticity
Advanced glycosylation end-products (AGEs)
- from spontaneous nonenzymatic glycation of proteins when sugars (glucose, fructose, ribose) react with lysine or arginine residues
- because of the low turnover, articular cartilage is susceptible to AGEs accumulation.
- accumulation of AGEs has been thought to play a role in the development of OA of the knee and ankle.
- effects of AGEs formation
  - modification of type II collagen by cross-linking of collagen molecules
    - increasing stiffness and brittleness
    - increasing susceptibility to fatigue failure

Factor	*Aging*	*Osteoarthritis*
Water	Decreased	Increased
Modulus/stiffness	Increased (less elastic)	Decreased (more elastic)
Chondrocytes	Fewer but increased size	Cells cluster (late stage)
Glycosaminoglycans	Increased keratan sulfate:chondroitin 4 sulfate ratio, constant chondroitin 6 sulfate	Increased chondroitin 4 sulfate:keratan sulfate ratio
Proteoglycans	Increased decorin, decreased proteoglycan size	Proteoglycans unbound from hyaluronate
Collagen	Increased collagen crosslinking/brittleness	Collagen disorganized (increased collagenase)
Advanced Glycosylation End products (AGE)	Increased	Accumulation of AGE thought to lead to OA knee and ankle

Healing in Articular Cartilage

Deep lacerations (through tidemark)
- leads to fibrocartilage healing
- occurs when laceration travels through tidemark and penetrates subchondral bone
- fibrocartilage produced by undifferentiated marrow mesenchymal stem cells
- a healing response is initiated with hematoma, stem cell migration, and vascular ingrowth.
- This response produces type I collagen and resultant fibrous cartilage rather than desired hyaline cartilage as produced by chondrocytes.
- This repair cartilage has diminished resiliency, stiffness, poor wear characteristics, and the predilection for arthritis.
Superficial laceration (not through tidemark)
- leads to chondrocytes proliferation but no healing takes place because of avascular nature of cartilage

Clinical Conditions

Articular Defects of the Knee (Adults)
Osteocondritis dissecans