Osteoarthritis

Question 1

What is the joint structure?

Answer 1

Bones with cartilage on the end (very thin)

In between in synovial fluid (fluid-filled capsule)

Synovial membrane surround the synovial fluid

Then tendons and muscle

Question 2

What is Osteoarthritis (OA)?

Answer 2

= chronic irreversible degenerative disease of articular cartilage

= one of the commonest morbidities in older people (esp. as life span is increasing)

= most frequently cited reason for restricted physical activity

= importantly it is more than just “wear and tear” of joints

= more common in females

= costs NHS ~£10 billion annually

Question 3

What is Primary vs Secondary OA?

Answer 3

Primary
= most common form found mainly in knee joints
= rare in people less than 40 (prevalence increases with age)
= genetic predisposition (differs amongst joints)
= gradual onset

Secondary
= often caused by trauma
= occurs in any joint

Question 4

What is the aeitology of OA?

Answer 4

Not completely understood (likely to be many causes)

Risk Factors
Environmental = overuse, occupation, weight, injury
Genetic = gender, age, genetics, family history, joint dysplasia

Question 5

How does Obesity relate to OA

Answer 5

= increased risk of OA with high BMI

= may be a risk factor due to elevated weight bearing

BUT = more complex
= suggests inflammatory response and adipose tissue is involved
(NOT just wear and tear of cartilage)

Question 6

What is Cartilage?

Answer 6

= aneural (no neurons)

= avascular (no blood supply)

= sparsely populated with cells

Composed mainly of:
= water (~75%)
= collagen II (structurally important)
= large proteoglycans (e.g. Aggrecan - holds water in place)
= small proteoglycans

cells made + broken down = remodelling
(very slow process as cells are far apart)

Question 7

How does Cartilage work?

Answer 7

When sitting
= no weight on cartilage of knee
= water sits in cartilage

When standing / walking
= weight rests on cartilage of knee
= pushes water out of cartilage into synovial gap (like a sponge)

Question 8

What are MMPs and Aggrecanase?

Answer 8

MMPs
= Matrix Metalloproteinases

MMPs + Aggrecanase
= attack components of cartilage
= (aggrecan and collagen)

= partially degraded aggrecan is lost from the tissue along with it’s functions
(aggrecan holds water that gives tissue compressive resistance)
+ not balanced out by synthesis of new aggrecan = OA

Question 9

What happens to the cartilage in OA?

Answer 9

In OA
= lose the capacity to hold water in cartilage
= loss of aggrecan associated
(imbalance between breakdown and synthesis = run out of cartilage = degeneration = OA)

Normally
= cartilage is normal thickness
= suface is smooth
= meniscus in intact

OA
= cartilage thinner than normal
= surface is rough
= meniscus is damaged or missing

Question 10

What is the meniscus?

Answer 10

Menisci (medial and lateral)
= rest between the tibial plateau and the femoral condyl
= play crucial role in knee joint
= involved in load transmission, shock absorption + lubrication

= meniscal damage is correlated with increased OA

Previously meniscus would be surgically removed
= BUT this led to OA development
= now it is repaired instead

Question 11

What is the balance involved in OA?

Answer 11

Balance between
= inhibiting anabolic processes / promoting catabolic processes
(Degradation - IL-1 and TNFα)

AND

= promoting anabolic processes / inhibiting catabolic processes
(Re-synthesis - IL-4, IL-10 and IL-13)

Question 12

How are pro-inflammatory influences involved?

Answer 12

= IL-1 and TNFα

= induce the production of other cytokines (IL-6 and IL-8)

= stimulate the activity of proteases

= promotes degradation / inhibits re-synthesis

= run out of cartilage

Question 13

How are anti-inflammatory influences involved?

Answer 13

= IL-4, IL-10 and IL-13

= inhibit production of pro-inflammatory cytokines: IL-1 and TNFα

= inhibit activity of proteases

= reduced protease production (MMPs - Matrix metalloproteinase)

= increase protease inhibitor production (TIMP - Tissue inhibitors of metalloproteinase)

= inhibits degradation / promotes re-synthesis

= cartilage increases

Question 14

What are some therapies for OA?

Answer 14

= intervention only deals with symptoms (pain management / joint replacement) not curing

NSAIDs (non-steroidal anti-inflammatory drugs)
= inhibit COX enzymes

= e.g. ibuprofen, naproxen, diclofenac = inhibit types 1 (constitutive) and type 2 (inducible)
= leads to unwanted outcomes

= e.g. specific COX-2 inhibitors
= e.g. Valdecoxib - Rofecoxib = shown to be better than placeba = didn’t end up working out

Injection
= cortisone or hyaluronan

Surgery
= resurface joint replacement

Question 15

What would be targets for future treatment options?

Answer 15

= treatment to delay or prevent the condition

= Neutralisation of IL-1 / TNFα effects

= Upregulation of anti-inflammatory cytokines

= Rebalancing of MMP / Aggrecanase and TIMP activity

Difficult though because
= by the time symptoms present = may be too late
= also need good biomarkers of articular cartilage breakdown as an early sign of OA

Question 16

EXTRA READING? Other treatment options?

Answer 16

Some developments in treatment options:

Gene therapy
= use virus to deliver gene that produces the protein Lubricin
= helps joints move smoothly in mice
= reduced pain and inflammation

Stem cell therapy
= to regenerate cartilage
= reduced pain and improved joint function

Wearable technology
= wearable devices that monitor joint movement and provide feeback to patients
= e.g. when knee is bending too far / too quickly

Dietary interventions
= some foods / supplements may alleviate OA symptoms
= e.g. omega-3-fatty acids reduce inflammation and improve joint function
= e.g. curcumin (in tumeric)