L12

Question 1

what are the features of Osteoarthritis (OA)

Answer 1

usually slow but progressive loss of ECM and the “chondrogenic
phenotype” in articular cartilage due to mechanical or
degradative damage without obvious cause (primary OA)

can occur as a result of injury

results in (severe) limitation in joint movement, joint deformity,
inflammation and severe pain that substantially reduces quality
of life

often associated with formation of new bone, incorrectly located

gene expression (reduced Sox-9)

Question 2

what stain is used to check for GAGs in cartilage, and what color does it produce

Answer 2

Safranin O

red

Question 3

what is ADAMTS-5

Answer 3

an aggrecanase

Question 4

what happens to OA when ADAMTS-5 is knocked out

Answer 4

gets reduced

Question 5

what is MMP-13

Answer 5

collagenase

Question 6

what happens to OA when MMP-13 is knocked out

Answer 6

gets reduced

Question 7

OA depends more on collagen cleavage than aggrecan destruction

Answer 7

true

Question 8

OA is polygenic and multifactorial

Answer 8

true

Question 9

what genes are linked to OA

Answer 9

GDF5 growth factor member of TGF-beta family important in ECM homeostasis

RUNX2 (6p 21.1) master transcription factor responsible for driving endochondrial ossification including MMP-13 expression

PTHLH (12p 11.22) encodes PTHrP chondrocyte growth factor driven by IHH secretion

SMAD3 intracellular signaling protein involved in TGF-beta production (induces ECM synthesis, reduces MMP expression)

Question 10

what are the Current therapies for OA

Answer 10

1. surgery
2. non-steroidal anti-inflammatories (do not stop disease progression and irreversible ECM loss/disability)
3. identify and target key proteinases

• ADAMTS-4/5 (aggrecan), MMP-13 (collagen)
  inhibited by TIMP-3
• still not fully known what else ADAMTS is required for. inhibitors may therefore be non-specific/make disease worse

4. Genetic screening may allow susceptible patients to have physiotherapy
   prior to disease onset

Question 11

what are the features of Rheumatoid arthritis (RA)

Answer 11

inflammatory

more common in younger patients than OA
approx. 400,000 in UK, more common amongst females (3:1)

progressive loss of ECM and chondrogenic phenotype in articular cartilage due to immune cell-mediated damage (genetic linkage to MHC; HLA-DR4 in particular)

results in (severe) limitation in joint movement, joint deformity,
inflammation and severe pain that substantially reduces quality
of life

autoimmune disease

Rheumatoid factor”(RF) discovered in blood of many RA patients

Question 12

what is RF

Answer 12

IgM that binds IgG (autoantibody)

Question 13

what MHC is linked to RA

Answer 13

HLA-DR4

Question 14

why does RF not cause RA

Answer 14

RF is found in healthy people

Question 15

what else, beside RF do RA patients have?

Answer 15

auto-antibodies reactive with a number of nuclear structural antigens that react with epitopes that contain citrullinated amino acids rather than conventional amino acids

Question 16

What are citrullinated amino acids

Answer 16

arginine converted to citrulline via the enzyme paddy

Question 17

what are anti-citrullinated peptide antibodies; ACPA

Answer 17

antibodies that are specific for epitopes from self-antigens that contain citrullinated
amino acids

Question 18

what is the percentage of RA patients that have ACPA

Answer 18

60

Question 19

what is the percentage of normal people that have ACPA

Answer 19

2

Question 20

what is RA characterized by

Answer 20

inflammation of the synovium

Question 21

how is RA characterization different to OA

Answer 21

RA is characterised by the presence of specific B and CD4 TH cell mediated autoimmunity

Question 22

what is the immunology of RA

Answer 22

inflammation in the synovial membrane attracts leukocytes into the tissue

autoreactive CD4 T cells activate macrophages producing pro inflammatory cytokines

cytokines induce production of MMP and RANK ligand by fibroblasts

MMPs attack tissues. joint destruction is caused by activation of bone-destroying osteoclasts

Question 23

What are the possible (candidate) autoantigens CD4+ TH cells may recognize in RA?

Answer 23

collagen
aggrecan

Question 23

what is CIA

Answer 23

collagen induced arthritis

Question 24

what is PGIA

Answer 24

proteoglycan induced arthritis

Question 25

what are the Current therapies for RA

Answer 25

1. non-steroidal anti-inflammatory drugs NSAID (do not stop disease progression and irreversible ECM loss/disability)
2. late 1980s, identification of TNF-a as a key target for therapy. 1992 introduction of Infliximab (monoclonal antibody that binds TNF-a and blocks its action) therapy for RA
3. 2004, monoclonal antibody Rituximab (specific for CD20 ) kills B cells. Used in those patients who do not respond to Infliximab
   treatment
4. better genetic/ACPA screening may allow susceptible patients to be identified earlier and so:
   • can have therapy at earlier time points
     (before disease manifests)
   • or can have different types of therapies