failure to maintain ECM homeostasis: arthritis Flashcards
lecture 12
What is the primary characteristic of OA in articular cartilage?
Progressive loss of ECM and the chondrogenic phenotype due to mechanical or degradative damage, often without an obvious cause (primary OA).
What are the key symptoms of OA?
Severe limitation in joint movement, joint deformity, inflammation, and pain, significantly reducing quality of life.
What is secondary OA?
OA that occurs as a result of an injury.
How common is OA in the UK?
8.75 million people have sought treatment, and it is most common in the elderly.
What percentage of knee replacements are due to OA?
97%
How does loading stress contribute to ECM homeostasis?
Loading stress produces ECM fragments that stimulate increased ECM synthesis, restoring a healthy matrix.
What are integrins, and how do they function in the ECM?
Integrins provide cell-ECM contact for structural strength and mediate cell signalling.
What role does ADAMTS-5 play in OA?
ADAMTS-5 is an aggrecanase responsible for degrading aggrecan. OA is reduced in ADAMTS-5 knockout models.
What is MMP-13, and what is its role in OA?
MMP-13 is a collagenase that degrades collagen. OA is virtually absent in MMP-13 knockout models.
How heritable is OA?
OA is 50% heritable but is polygenic and multifactorial.
Name four genes associated with OA and their roles.
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.
What are the limitations of current OA therapies?
There is no cure, and treatments like NSAIDs don’t stop disease progression or prevent irreversible ECM loss and disability.
What are potential targets for future OA therapies?
Proteinases such as ADAMTS-4/5 (aggrecan) and MMP-13 (collagen), though inhibitors may have off-target effects.
How might genetic screening help OA patients?
It may identify at-risk individuals for early physiotherapy to delay disease onset.
What is RA, and how does it differ from OA?
RA is a chronic inflammatory autoimmune disease that affects younger patients, whereas OA is typically mechanical and degenerative, common in the elderly.
What causes ECM loss in RA?
Immune cell-mediated damage linked to genetic factors such as MHC (HLA-DR4).
What is rheumatoid factor (RF)?
RF is an IgM autoantibody that binds IgG, identified in RA patients.
What are anti-citrullinated protein antibodies (ACPA)?
Autoantibodies that target self-antigens containing citrullinated amino acids, present in 60% of RA patients.
How are citrullinated amino acids formed?
Arginine is converted to citrulline by the removal of an NH group via an enzyme.
What triggers the autoimmune response in RA?
An unknown trigger causes inflammation in the synovial membrane, attracting leukocytes and initiating immune-mediated damage.
How do autoreactive CD4 T cells contribute to RA?
They activate macrophages, leading to pro-inflammatory cytokine production and sustained inflammation.
What role do cytokines play in RA pathogenesis?
Cytokines induce fibroblasts to produce MMPs and RANK ligands, which degrade tissues and activate bone-destroying osteoclasts.
What are the potential autoantigens recognised by CD4 T cells in RA?
Collagen, aggrecan, and proteoglycans.
How is RA linked to genetic factors?
RA is polygenic and associated with genes like HLA-DR4, which contribute to the autoimmune response.
What are the primary symptoms of RA?
Joint deformity, inflammation, pain, and severe limitation in movement.
What surgical intervention is commonly used for OA?
Knee replacements, often necessitated by severe OA.
How do NSAIDs help in OA and RA?
They reduce inflammation but do not stop disease progression or ECM loss.
What is infliximab, and how is it used in RA?
A monoclonal antibody that binds TNF-α to block its action, reducing inflammation in RA patients.
What is rituximab, and when is it used?
A CD20-specific monoclonal antibody that kills B cells, used in RA patients unresponsive to TNF-α inhibitors.
How might better genetic screening improve RA outcomes?
It could identify susceptible patients earlier for preventative or tailored therapies.
What are the primary proteinases targeted in OA therapies?
ADAMTS-4/5 (aggrecanases) and MMP-13 (collagenase).
What role does TIMP-3 play in OA?
It inhibits ADAMTS-4/5 and MMP-13, potentially reducing ECM breakdown.
Why is TNF-α a key target in RA therapy?
It is a pro-inflammatory cytokine that drives inflammation and joint damage in RA.
How do ACPA affect RA progression?
ACPA-targeted citrullinated proteins contribute to immune activation and joint damage.
What is the role of RUNX2 in ECM homeostasis?
It regulates MMP-13 expression and drives endochondral ossification, crucial for ECM turnover.
