LOCO Osteoarthritis

Question 1

Risk Factors of Osteoarthritis

Answer 1

Extrinsic
•	Occupational exposures
•	Past joint injury. 
•	Physical activity levels
•	High BMI (repetitive strain)  

Intrinsic
•	Infection.
   o	   (Cytokines such as IL-1, IL-6 and TNFa cause an increase in catabolism) 
•	Congenital abnormalities.
   o	   Malalignment
•	Past joint surgery.

Systemic
• Age.
• Female
• Genetics

Question 2

What genes can predispose to Osteoarthritis

Answer 2

7q22: loss of GPCR22 –> increase risk of knee OA progression

DOT1L: (enzyme involve in histone methylation) master protector of chondrocytes.

GLN3/GLT8D1: guanine nucleotide binding protein.

GDF5: growth differentiation factor 5

ASTN2: astrotactin 2 may be involved with pain and neuronal adhesion.

Question 3

Mechanism of Age and Repetitive strain

Answer 3

1. Repetitive (excess) mechanical loading that stresses chondrocyte
2. These repair damage to cartilage, but are accumulating stress induced signals over their lifetime
   a. Make less proteoglycans
   b. Increased production of collage type 1
3. Therefore older chondrocytes have a heaver load of reactive oxidative species that can damage the DNA, are more likely to undergo apoptosis
4. Release degrading enzyme and cause damage to the cartilage.

Question 4

Genetic Bases in Pathogenesis

Answer 4

HMGB2 = high mobility group protein 2
o Chromatin protein that regulates DNA of histones that is uniquely expressed in superficial zone chondrocytes

Loss of HMBG2 = superficial zone cell death
o Loss of progenitor cells

Therefore reduced synthesis of ECM components

Question 5

Break down of cartilage and associated Inflammation

Answer 5

1. As chondrocytes become weaker, break off into synovial fluid = joint mice.
   a. Type A synoviocytes attempt to remove this –> recruit inflammatory factors
2. Lead to the release of pro-inflammatory cytokines (IL-1, IL-6, TNFa).
   a. These cause inflammation of the synovium (synovitis).
   b. These damage the cartilage and lead to fibrillation.
   c. Eventually this leads to
   eburnation.

Question 6

Subchondral Bone

Answer 6

As articular cartilage is eroded underlying bone is exposed.
o Micro fractures of trabeculae (synovial fluid enters)

Subchondral sclerosis: increased osteoblastic activity and new bone formation.
(bone tries to make itself thicker)

Subarticular cysts: surface undergoes focal pressure necrosis.

Vascular engorgement: slows blood flow and there is bone marrow oedema.

Question 7

Features of OA - Macro and microscopically

Answer 7

Macroscopically
3 phases of degeneration:
1) Fibrillation.
a) Instrinsic/extrinsic stimuli –> roughening of parts of cartilage causing cracks on surface

2) Erosion and cracking.
a) Synovial fluid enters cracks and widens them.
b) Eventually cracks will cause parts of the cartilage to break off and gaps widen for bone to bone contact

3) Eburnation.
a) Polishing of the bone in bone to bone contact.

Microscopically
• Chondrocyte Necrosis.
o More marked in superficial layers

• Focal Clumps or Clones of Chondrocytes.
o Rather than being stacked: chondrocytes form groups (known as isogenic clusters)

• Change to fibrocartilage from hyaline.
o Chondrocytes start to produce other collagen –> Changes the makeup of the ECM.
 More type I is produced –> More fibrocartilage.
o Duplication in tide mark.
 Chondrocytes die and enzymes/vesicles released which cause calcification higher in the articular cartilage
o Thickens calcified cartilage
 Makes underlying bone react –> Vascular invasion/engorgement

Question 8

Biochemical Features of OA

Answer 8

In early stages cartilage thickens and swells.
o Increases water.

But loss of proteoglycans make it less compatible.
o Water moves in and out fast.

Collagen lost
o Due to enzymes released from stressed chondrocytes and synovial membrane cells.
 MMPs, collagenases.

Cartilage softens and progresses to fibrillation.

Question 9

Stages of OA

Answer 9

Early
• Characterized by loss of superficial zone and
• Changes to the ECM of the articular cartilage.
• Cell clusters emerge

Late
• Continued loss of ECM and chondrocyte hypertrophy.