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PATH30001 - Mechanisms of Disease > Lecture 13 - Osteoarthritis > Flashcards

Lecture 13 - Osteoarthritis Flashcards

1
Q

Who does osteoarthritis primarily affect?

A

The elderly

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2
Q

Who gets arthritis?

What is the prevalence?

A
  • 1 in 10 people
  • The elderly
  • Animals
  • Kids: juvenile idiopathic arthritis
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3
Q

Which is more prevalent; Rheumatoid or osteoarthritis?

A

Osteoarthritis

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4
Q

What is the main feature of osteoarthritis?

A

Destruction of articular cartilage

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5
Q

Compare osteo and rheumatoid arthritis:
• Synovial inflammation
• Bone
• Cartilage

A

Rheumatoid has much inflammation, while osteo- has very little

Rheu.: bone thins, osteo: bone thickens, + spurs

Cartilage: destroyed in both

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6
Q

Describe the cartilage in a joint.

What are the functions?

A

Articular cartilage, very smooth surface at the articulation of the bones
• shock absorption
• lubrication

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7
Q

What is articular cartilage made up of?

What does it lack?

A
  • 90% water
  • collagen
  • ECM components: aggrecans etc.

• chondrocytes

Lacks:
• blood supply
NB almost acellular

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8
Q

Describe collagen organisation in articular cartilage, through to the bone

A
  1. Superior: tight parallel arrangement
  2. Middle: mesh
  3. Deep: loose, perpendicular to superior layer
  4. Calcified cartilage (transition zone)
  5. Sub-chondral bone
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9
Q

Describe the presence of cells in articular cartilage

A
  • Very few cells, and they are exclusively chondrocytes

* very sparse, not touching each other

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10
Q

Describe the structure of collagen

A

Three alpha helices → triple helix

Gly-X-Y repeating subunits

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11
Q

What are the two broad categories of collagen?

A
  • Fibrillar

* Amorphous

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12
Q

Which types of collagen are fibrillar?

A

I, II & III

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13
Q

Where is fibrillar collagen found?

What is its function in these tissues?

A 
Type I & III:
 • Tendons
 • Bone
 • Ligament
 • Skin

Type II:
• articular cartilage
(almost exclusively)

Provides tensile strength

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14
Q

Outline the biosynthesis of collagen

A
  1. Translation of RNA, fed into Golgi
  2. Signal peptide removed
  3. Hydroxylation (to form hydroxy-proline etc.)
  4. Glycosylation
  5. The three chains align
  6. Winding of chains to form the triple helix (from C to N terminus)
  7. Exocytosis through secretory pathway
  8. N and C-termini are cleaved by ADAMTS
    → COLLAGEN MOLECULES
  9. Lateral association of collagen molecules, covalent cross linking
    → COLLAGEN FIBRILS
  10. Aggregation of fibrils
    → COLLAGEN FIBRES
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15
Q

What is the function of ADAMTS?

A

Enzymes that cleave the N and C termini of collagen triple helices

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16
Q

What are the phases of collagen?

A
  1. Procollagen
  2. Collagen molecules
  3. Collagen fibrils
  4. Collagen fibres
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17
Q

Which other type of collagen associates with Type II collagen?
Describe this association?

A

Type IX collagen

• fibrils associate with the type II fibres

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18
Q

What are the features of proteoglycans?

A
  • Protein core

* Glucosaminoglycan chains

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19
Q

What is an important proteoglycan?

A

Aggrecan

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20
Q

Describe the formation of glycosaminoglycan subunits

A

e.g.
Glucose + oxygen group
→ glucuronic acid

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21
Q

What are some common substrates for glycosaminoglycans?

What are the two groups?

A 
Hexuronic acid:
 • GlcUA
 • IdUA
Hexosamine:
 • GlcNAc
 • GalNAc
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22
Q

What do you get when you combine a Hexuronic acid and Hexosamine?

A

A disaccharide

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23
Q

How do you get a glycosaminoglycan?

A

Chain of repeating disaccharides

24
Q

What sort of groups are commonly found on glycosaminoglycans?
Why?

A

Sulfate groups

Sulfate groups are critical for the function of proteoglycans as shock absorbers

25
Describe the presence of sulfate groups on glycosaminoglycans?
Highly variable and heterogeneous
26
Which glycosaminoglycans are found on aggrecan?
* Chondroitin sulfate * Keratan sulphate * Hyaluronan
27
Describe the structure of aggrecan
* 100 GAG chains * which are attached to a protein core * G1: binds aggrecan to hyluronan, immobilises aggrecan * G2 domain (?) * G3 domain: ligand binding * Interglobular domain (IGD)
28
What is the charge of aggrecan? | How does this arise?
Negatively charged The sulfate groups on the disaccharides have a negative charge. Thus, there are countless disaccharides per monomer.
29
How is the negative charge of aggrecan handled?
Cations attracted → H20 drawn in
30
What is hyaluronan?
* Central core, binding the G1 regions of many aggrecans | * this stabilises the aggrecans
31
What are the functions of the three G domains in aggrecan?
G1: attachment to HA G2: ? G3: ligand binding
32
What is IGD? | What are the features of it?
* Interglobular domain | * susceptible to proteinases
33
What is the business end of the aggrecan molecule?
The end, where all the GAGs are (i.e. where the negative charges are)
34
What happens if enzymes cleave at the IGD?
The 'business end' of the molecule is lost from the G1 domain
35
Describe the changes to aggrecan aggregates over time
Over the course of one's life, the aggregates become smaller, with fewer aggrecan monomers
36
Describe the result of type II collagen and aggrecan working together
Collagen: shape & tensile strength Aggrecan: swelling pressure Together they confer resistance of compressive forces
37
What is the effect of papain?
Cleavage of IGD Collagen remains intact → Degradation of aggrecan
38
Which enzymes are aggrecanases?
ADAMTS-4 | ADAMTS-5
39
What is important about ADAMTS-5?
It is the aggrecanase that destroys aggrecan in athritis
40
Describe the structure of a synovial joint
* Fibrous capsule * Synovium (thin membrane that secretes synovial fluid) * Synovial fluid * Articular cartilage
41
How long can subclinical osteoarthritis last?
Up to 10 years
42
What features are seen in the joint in mild OA?
* Osteophytes * Thinning and tearing of the cartilage * Midly inflamed synovium * Thickened capsule
43
What features are seen in the joint in severe OA?
* Joint space narrowing * Extensive cartilage erosion * Inflamed synovium * Osteophytes * Bone angulation
44
What are the aetiologies of OA?
1. Normal load on abnormal joints | 2. Abnormal load on normal joints
45
What are some risk factors for osteoarthritis? What are the two categories of risk factors?
Non-modifiable: • Old age • Genetics • Gender ``` Potentially modifiable: • Joint injury • Joint overload (body mass) • Muscle weakness • Joint mal-alignment • Heavy load carrying ```
46
Describe the pathogenesis of osteoarthritis
1. Risk factors for OA 2. Biochemical pathways • i.e. activation of ADAMTS-5 3. Cleavage of aggrecan at IGM 4. Destruction of articular cartilage
47
Describe the effect of being overweight on OA
Overweight people: doubled risk | Obese people: quadrupled risk
48
Which molecules are involved in the biochemical pathways leading to OA?
* Cytokines * Adipokines * Proteinases
49
Describe the risk factor of injury and joint trauma
Injury to joint WILL lead to OA | • there is no evidence that surgery prevents the onset of OA
50
Describe the risk factor of mal-alignment
Varus (bow legs) • high risk of knee OA Valgus (knock knees) • lower risk of OA than vargus
51
What happens when we wear high heel shoes?
* Shifts the body's centre of gravity | * predisposes to OA
52
What are the treatments for OA? | What are the categories?
Symptom modifiers • Analgesics, NSAIDs • Glucosamine • HA injections In the future: Disease modifiers • Anti-IL-1 • Gene therapy
53
What are DMOADs?
Disease modifying OA drugs * hope for these types of drugs in the future * don't have any at the moment * difficult, because there aren't any bio-markers
54
What are the first line therapies for OA?
* Exercise * Weight loss * Information
55
What type of molecule is hyaluronan?
A glycosaminoglycan

PATH30001 - Mechanisms of Disease (34 decks)

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