Normal and Abnormal Synovial Joint: Pathogenesis of OA

Question 1

What are the 3 features of the synovial joint?

Answer 1

• fibrous joint capsule
• articular (hyaline) cartilage (frictionless movement, shock absorber)
• calcified layer (attaches underlying bone)

Question 2

What is the role of the articular cartilage?

Answer 2

• elastic
• resilient
• shock absorber

Question 3

What synthesises the ECM?

Answer 3

chondrocytes

Question 4

What are chondrocytes?

Answer 4

• secrete and sit inside ECM

- change shape through different layers

Question 5

What are the 3 layers of the chondrocytes?

Answer 5

• tangenital (superficial, small flattened chondrocytes, proliferate = renewed ECM and cartilage, no blood supply and nutrients from synovial fluid)
• transitional (middle, bigger and rounder, produce more ECM as more active)
• radial (deep, hypertrophy and proliferate = stacks)

Question 6

What is the function of a chondrocyte?

Answer 6

• regulate synthetic and catabolic processes
• establish microenvironment around them
• within lacuna
• low mitochondria no. as low oxygen consumption
• low cell division, in response to injury/disease

Question 7

What are the features of the ECM of cartilage?

Answer 7

• 80% water
• proteoglycans (negative charge draws water into cartilage forming ground substances, regulates compressibility)
• collagen type II (holds proteoglycans in place through fibril network, makes proteoglycan pockets, compressive strength, regulates water in cartilage)
• lacks blood and sympathetic vessels, no nerve supply

Question 8

What does ECM survival depend on?

Answer 8

• diffusion of nutrients and metabolites through matrix

- fine balance between anabolism and catabolism

Question 9

What is the orientation of the 3 chondrocyte layers?

Answer 9

• tangenital (superficial) -> fibres lined up with surface of articular cartilage = highly tensile and gliding
• transitional (middle) -> haphazard and criss-crossed oblique = compression
• deep zone -> stacked up and perpendicular

Question 10

Where is type II collagen?

Answer 10

• all layers but more in superficial

Question 11

Where is type X collagen?

Answer 11

• more in calcified deep layers

Question 12

What are proteoglycans?

Answer 12

• exist as aggregates (aggrecan)
• core protein hyaluronan with GAG side chains linked by glycoproteins
• GAGs = keratin sulphate and chrondroitin sulphate

Question 13

What are the extrinsic risk factors of OA?

Answer 13

• occupational exposures
• high BMI
• past joint injury
• physical activity levels

Question 14

What are the intrinsic risk factors of OA?

Answer 14

• infection
• congenital abnormalities
• past joint surgery

Question 15

What are the genes involved in OA?

Answer 15

• 7q22
• DOT1L
• GLN3/GLT8D1
• GDF5
• ASTN2

Question 16

What is the role of pro-inflammatory cytokines?

Answer 16

• chondrocyte damage = mild inflammatory reaction
• stimuli cause release of cytokines = cartilage damage
• vicious cycle of inflammation
• major cause of pain
• pain felt in nearby tissues where nerve supply pain is associated as cartilage has no nerve supply
  = synovitis secondary to bone and cartilage pathology = pain and function loss

Question 17

What is the pathology of OA?

Answer 17

• age and repetitive strain
• excess mechanical loading stresses chondrocytes
• older chondrocytes have heavier load of reactive oxidative species which damage DNA = release degrading enzyme = cartilage damage

Question 18

What is HMGB2?

Answer 18

• high mobility group protein 2
• chromatin protein regulates DNA of histones expressed in superficial zone chondrocytes
• support chondrocyte survival
• regulates specific differentiation status of superficial zone cells
• loss = superficial zone cell death as progenitor cell loss and reduced ECM synthesis

Question 19

What are the 3 phases of articular degeneration macroscopically?

Answer 19

• fibrillation (intrinsic and extrinsic stimuli, roughening of cartilage parts = cracks)
• erosion and cracking (synovial fluid enters cracks widening them, eventually cartilage breaks off and gaps widen for bone and bone to contact)
• eburnation (polishing of bone in bone)

Question 20

What are the microscopic phases of articular degeneration?

Answer 20

• chondrocyte necrosis (superficial layers)
• focal clumps/clones of chondrocytes (isogenic clusters instead of stacks)
• fibrocartilage from hyaline (changes ECM so more type I, release of vesicles causing calcification, thickens calcified cartilage = vascular invasion of underlying bone)

Question 21

What are the biochemical changes?

Answer 21

• cartilage thickens and swells = increased water
• proteoglycan loss = less compatible
• collagen loss as enzymes released from stressed chondrocytes (collagenases)
• cartilage softens and progresses to fibrillation

Question 22

What are the 2 stages of OA?

Answer 22

Early
- loss of superficial zone
- ECM changes of articular cartilage
- cell clusters emerge
Late
- continued loss of ECM and chondrocyte hypertrophy

Question 23

What happens to subchondral bone?

Answer 23

• underlying bone exposed as articular cartilage eroded
• microfractures of trabeculae so synovial fluid enters
• subchondral sclerosis = increased osteoblastic activity and new bone formation
• subarticular cysts = surface undergoes focal pressure necrosis
• vascular engorgement = slows blood flow so bone marrow oedema