Lecture 7: Osteoarthritis

Question 1

Describe the overview of the knee joint structure

Answer 1

couple of millimetres layer of cartilage at end of long bones
- femoral condyl sites on top of tibial plateau

Synovial fluid bounded by synovial membrane

2 menisci rest between the tibial plateau and the femoral condyl

Question 2

True or false: cartilage is turned over?

Answer 2

True (slow breakdown and new cartilage re-synthesised)

Question 3

In general terms, what causes OA?

Answer 3

The breakdown of cartilage (when catabolic process of cartilage breakdown occurs at a faster rate than anabolic process of cartilage re-synthesis = re-modelling not happening or happening too slowly)

Question 4

True or false: OA is a chronic reversible degenerative disease?

Answer 4

False: it is a chronic irreversible degenerative disease of cartilage

Question 5

What is the impact of OA on individuals quality of life?

Answer 5

OA affects a large proportion of the population (particularly a disease associated with the older population)
causes morbidity in older people particularly
- significant joint pain results in reduced physical activity and mobility
–> sedentary lifestyle - not good for health

Question 6

What are the two different types of OA and how do they differ?

Answer 6

Primary OA
- more common with increases in age over 40
- most commonly found in knee joint
- there is a genetic predisposition

Secondary OA
- caused by trauma and can occur in any joint

Question 7

True or false: genetic predisposition to development of OA differs amongst joints?

Answer 7

True

Question 8

True or false: there is a higher prevalence of musculoskeletal conditions in females than males?

Answer 8

True

Question 9

Why is it imperative to understand the condition and ways to treat it?

Answer 9

A large proportion of the population is affected - commonest cause of morbidity in the older population
has a massive economic burden (loss of work, treatment)
We have no cure

Question 10

what is the aetiology of OA (including the modifiable and non-modifiable risk factors)?

Answer 10

No known cause but risk factors include:
- gender, age, genetics –> non-modifiable
- occupation, weight (elevated BMI) –> modifiable

Question 11

How does a higher BMI increase risk of developing OA?

Answer 11

• increased adipose tissue and adipocytes that generate an inflammatory response = pro-inflammatory response leads to OA

Question 12

About 50% of the risk of developing OA is due to what?

Answer 12

A genetic predisposition

Question 13

Describe the structure and function of cartilage

Answer 13

Structure:
- Aneural, avascular (gas exchange and nutrient exchange occurs by diffusion so is slow) and sparsely populated with cells
- Composed mainly of: water, collagen II fibres, large proteoglycans (E.g. aggrecan) and small proteoglycans

Function:
- when standing/walking, pressure is applied to the cartilage, the water is being forced out of the cartilage, proteoglycans such as aggrecan acts to pull the water back into the cartilage by osmotic force = equilibrium established to support weight

Question 14

What the dominant proteoglycan present in cartilage and what is its role?

Answer 14

Aggrecan provides osmotic pressure to draw water back into the cartilage opposing the force of pressure applied under body weight giving the tissue compressive resistance

Question 15

What is the effect of aggrecan deficiency in cartilage?

Answer 15

• reduced aggrecan in cartilage = reduced ability to draw water back into cartilage - loss of water from cartilage, degradation of cartilage
• eventually bones will be in contact

Question 16

True or false: a loss of aggrecan is associated with OA?

Answer 16

True (can occur many years before the diagnosis of OA - opportunities to intervene before symptoms occur)

Question 17

What is the role of matrix metalloproteinases (MMPs) and aggrecanase?

Answer 17

responsible for the catabolic breakdown of aggrecan and collagen in cartilage - needed for normal tissue remodelling and turnover (useful when balanced with anabolic synthesis)

Question 18

What is the role of the menisci?

Answer 18

involved in load transmission, shock absorption and lubrication
- femoral condyl sits on the menisci to distribute the load

Question 19

How does meniscal damage correlate with OA incidence?

Answer 19

Meniscal damage is correlated with increased incidence of OS

(the correlation between a complete menisectomy and development of OA was 1 - i.e. everybody developed OA - hence why damaged menisci are not removed anymore but repaired instead)

Question 20

Give two examples of molecules that inhibit anabolic process and promote degradative catabolic process and how does this drive development of OA?

Answer 20

IL-1
TNF-alpha

Drives development of OA by:
- promote a pro-inflammatory environment (induce production of other cytokines)
- stimulates the activity of proteases (MMPs and Aggrecanase)
- gradual reduction of aggrecan abundance and loss of function

Question 21

Give two examples of molecules that promote anabolic process and inhibit degradative catabolic process and how does this prevent development of OA?

Answer 21

IL-4
IL-10
IL-13

Prevents development of OA by:
- inhibit production of pro-inflammatory cytokines IL-1 and TNF-alpha
- inhibit activity of proteases (MMPs and Aggrecanase)
- increase synthesis of protease inhibitor (TIMP)

Question 22

What is the role of TIMP?

Answer 22

Tissue inhibitors of metalloproteinase (TIMP) - inhibit activity of MMPs that would otherwise degrade the cartilage

Question 23

True or False: OA can be treated with inhibitors of IL-1 and TNF-alpha?

Answer 23

These therapeutics have not shown to be particularly successful in treating OA
- partly due to complexity of OA

Question 24

How can OA be treated?

Answer 24

Intervention deals with symptom management since there is no cure
- NSAIDs (short-term use is okay) that inhibit COX enzymes to reduce production of prostaglandins involved in inflammation
- Intra-articular injection - cortisone or hyaluronan injected into the synovial space to physically push the joints apart (temporary fix and painful)
- Joint replacement - good outcomes and very successful approach

Question 25

What are some emerging approaches that may be used in the treatment of OA?

Answer 25

Treatments to delay or prevent OA are being examined:
- Neutralisation of IL-1 and/or TNF-alpha effects
- upregulation of anti-inflammatory cytokines
- rebalancing of MMP/aggrecanase and TMP activity

Issue with these approaches are that these changes occur years before the onset of symptoms so difficult to know who to treat
- need good biomarkers of articular cartilage breakdown as an early sign of OA in order to intervene earlier and slow proression.