failure to maintain ECM homeostasis: arthritis

Question 1

What is the primary characteristic of OA in articular cartilage?

Answer 1

Progressive loss of ECM and the chondrogenic phenotype due to mechanical or degradative damage, often without an obvious cause (primary OA).

Question 2

What are the key symptoms of OA?

Answer 2

Severe limitation in joint movement, joint deformity, inflammation, and pain, significantly reducing quality of life.

Question 3

What is secondary OA?

Answer 3

OA that occurs as a result of an injury.

Question 4

How common is OA in the UK?

Answer 4

8.75 million people have sought treatment, and it is most common in the elderly.

Question 5

What percentage of knee replacements are due to OA?

Answer 5

97%

Question 6

How does loading stress contribute to ECM homeostasis?

Answer 6

Loading stress produces ECM fragments that stimulate increased ECM synthesis, restoring a healthy matrix.

Question 7

What are integrins, and how do they function in the ECM?

Answer 7

Integrins provide cell-ECM contact for structural strength and mediate cell signalling.

Question 8

What role does ADAMTS-5 play in OA?

Answer 8

ADAMTS-5 is an aggrecanase responsible for degrading aggrecan. OA is reduced in ADAMTS-5 knockout models.

Question 9

What is MMP-13, and what is its role in OA?

Answer 9

MMP-13 is a collagenase that degrades collagen. OA is virtually absent in MMP-13 knockout models.

Question 10

How heritable is OA?

Answer 10

OA is 50% heritable but is polygenic and multifactorial.

Question 11

Name four genes associated with OA and their roles.

Answer 11

GDF5: Important for ECM homeostasis.
**RUNX2: **Drives endochondral ossification, including MMP-13 expression.
PTHLH: Encodes PTHrP, a chondrocyte growth factor driven by IHH secretion.
**SMAD3: **Involved in TGF-β signalling and production.

Question 12

What are the limitations of current OA therapies?

Answer 12

There is no cure, and treatments like NSAIDs don’t stop disease progression or prevent irreversible ECM loss and disability.

Question 13

What are potential targets for future OA therapies?

Answer 13

Proteinases such as ADAMTS-4/5 (aggrecan) and MMP-13 (collagen), though inhibitors may have off-target effects.

Question 14

How might genetic screening help OA patients?

Answer 14

It may identify at-risk individuals for early physiotherapy to delay disease onset.

Question 15

What is RA, and how does it differ from OA?

Answer 15

RA is a chronic inflammatory autoimmune disease that affects younger patients, whereas OA is typically mechanical and degenerative, common in the elderly.

Question 16

What causes ECM loss in RA?

Answer 16

Immune cell-mediated damage linked to genetic factors such as MHC (HLA-DR4).

Question 17

What is rheumatoid factor (RF)?

Answer 17

RF is an IgM autoantibody that binds IgG, identified in RA patients.

Question 18

What are anti-citrullinated protein antibodies (ACPA)?

Answer 18

Autoantibodies that target self-antigens containing citrullinated amino acids, present in 60% of RA patients.

Question 19

How are citrullinated amino acids formed?

Answer 19

Arginine is converted to citrulline by the removal of an NH group via an enzyme.

Question 20

What triggers the autoimmune response in RA?

Answer 20

An unknown trigger causes inflammation in the synovial membrane, attracting leukocytes and initiating immune-mediated damage.

Question 21

How do autoreactive CD4 T cells contribute to RA?

Answer 21

They activate macrophages, leading to pro-inflammatory cytokine production and sustained inflammation.

Question 22

What role do cytokines play in RA pathogenesis?

Answer 22

Cytokines induce fibroblasts to produce MMPs and RANK ligands, which degrade tissues and activate bone-destroying osteoclasts.

Question 23

What are the potential autoantigens recognised by CD4 T cells in RA?

Answer 23

Collagen, aggrecan, and proteoglycans.

Question 24

How is RA linked to genetic factors?

Answer 24

RA is polygenic and associated with genes like HLA-DR4, which contribute to the autoimmune response.

Question 25

What are the primary symptoms of RA?

Answer 25

Joint deformity, inflammation, pain, and severe limitation in movement.

Question 26

What surgical intervention is commonly used for OA?

Answer 26

Knee replacements, often necessitated by severe OA.

Question 27

How do NSAIDs help in OA and RA?

Answer 27

They reduce inflammation but do not stop disease progression or ECM loss.

Question 28

What is infliximab, and how is it used in RA?

Answer 28

A monoclonal antibody that binds TNF-α to block its action, reducing inflammation in RA patients.

Question 29

What is rituximab, and when is it used?

Answer 29

A CD20-specific monoclonal antibody that kills B cells, used in RA patients unresponsive to TNF-α inhibitors.

Question 30

How might better genetic screening improve RA outcomes?

Answer 30

It could identify susceptible patients earlier for preventative or tailored therapies.

Question 31

What are the primary proteinases targeted in OA therapies?

Answer 31

ADAMTS-4/5 (aggrecanases) and MMP-13 (collagenase).

Question 32

What role does TIMP-3 play in OA?

Answer 32

It inhibits ADAMTS-4/5 and MMP-13, potentially reducing ECM breakdown.

Question 33

Why is TNF-α a key target in RA therapy?

Answer 33

It is a pro-inflammatory cytokine that drives inflammation and joint damage in RA.

Question 34

How do ACPA affect RA progression?

Answer 34

ACPA-targeted citrullinated proteins contribute to immune activation and joint damage.

Question 35

What is the role of RUNX2 in ECM homeostasis?

Answer 35

It regulates MMP-13 expression and drives endochondral ossification, crucial for ECM turnover.