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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
Q

Describe the presence of sulfate groups on glycosaminoglycans?

A

Highly variable and heterogeneous

26
Q

Which glycosaminoglycans are found on aggrecan?

A
  • Chondroitin sulfate
  • Keratan sulphate
  • Hyaluronan
27
Q

Describe the structure of aggrecan

A
  • 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
Q

What is the charge of aggrecan?

How does this arise?

A

Negatively charged

The sulfate groups on the disaccharides have a negative charge.

Thus, there are countless disaccharides per monomer.

29
Q

How is the negative charge of aggrecan handled?

A

Cations attracted

→ H20 drawn in

30
Q

What is hyaluronan?

A
  • Central core, binding the G1 regions of many aggrecans

* this stabilises the aggrecans

31
Q

What are the functions of the three G domains in aggrecan?

A

G1: attachment to HA
G2: ?
G3: ligand binding

32
Q

What is IGD?

What are the features of it?

A
  • Interglobular domain

* susceptible to proteinases

33
Q

What is the business end of the aggrecan molecule?

A

The end, where all the GAGs are (i.e. where the negative charges are)

34
Q

What happens if enzymes cleave at the IGD?

A

The ‘business end’ of the molecule is lost from the G1 domain

35
Q

Describe the changes to aggrecan aggregates over time

A

Over the course of one’s life, the aggregates become smaller, with fewer aggrecan monomers

36
Q

Describe the result of type II collagen and aggrecan working together

A

Collagen: shape & tensile strength
Aggrecan: swelling pressure

Together they confer resistance of compressive forces

37
Q

What is the effect of papain?

A

Cleavage of IGD
Collagen remains intact

→ Degradation of aggrecan

38
Q

Which enzymes are aggrecanases?

A

ADAMTS-4

ADAMTS-5

39
Q

What is important about ADAMTS-5?

A

It is the aggrecanase that destroys aggrecan in athritis

40
Q

Describe the structure of a synovial joint

A
  • Fibrous capsule
  • Synovium (thin membrane that secretes synovial fluid)
  • Synovial fluid
  • Articular cartilage
41
Q

How long can subclinical osteoarthritis last?

A

Up to 10 years

42
Q

What features are seen in the joint in mild OA?

A
  • Osteophytes
  • Thinning and tearing of the cartilage
  • Midly inflamed synovium
  • Thickened capsule
43
Q

What features are seen in the joint in severe OA?

A
  • Joint space narrowing
  • Extensive cartilage erosion
  • Inflamed synovium
  • Osteophytes
  • Bone angulation
44
Q

What are the aetiologies of OA?

A
  1. Normal load on abnormal joints

2. Abnormal load on normal joints

45
Q

What are some risk factors for osteoarthritis?

What are the two categories of risk factors?

A

Non-modifiable:
• Old age
• Genetics
• Gender

Potentially modifiable:
 • Joint injury
 • Joint overload (body mass)
 • Muscle weakness
 • Joint mal-alignment
 • Heavy load carrying
46
Q

Describe the pathogenesis of osteoarthritis

A
  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
Q

Describe the effect of being overweight on OA

A

Overweight people: doubled risk

Obese people: quadrupled risk

48
Q

Which molecules are involved in the biochemical pathways leading to OA?

A
  • Cytokines
  • Adipokines
  • Proteinases
49
Q

Describe the risk factor of injury and joint trauma

A

Injury to joint WILL lead to OA

• there is no evidence that surgery prevents the onset of OA

50
Q

Describe the risk factor of mal-alignment

A

Varus (bow legs)
• high risk of knee OA

Valgus (knock knees)
• lower risk of OA than vargus

51
Q

What happens when we wear high heel shoes?

A
  • Shifts the body’s centre of gravity

* predisposes to OA

52
Q

What are the treatments for OA?

What are the categories?

A

Symptom modifiers
• Analgesics, NSAIDs
• Glucosamine
• HA injections

In the future:
Disease modifiers
• Anti-IL-1
• Gene therapy

53
Q

What are DMOADs?

A

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
Q

What are the first line therapies for OA?

A
  • Exercise
  • Weight loss
  • Information
55
Q

What type of molecule is hyaluronan?

A

A glycosaminoglycan

PATH30001 - Mechanisms of Disease (34 decks)

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