Osteoarthritis Flashcards
LO
- To know the pathological features of OA
- To understand the key pathways and cell types that mediate OA joint pathology
- To understand why obesity is a risk factor for OA
- To understand the relationship between OA joint inflammation and joint pain
What are common osteoarthritis sites?
- knee
- hip
- neck
- spine
- hand
- big toe
What can be seen on the x-ray of an osteoarthritic patient?
(3 clincial features of OA)
- loss of cartilage
- narrowing of joint space
- bony spurs (osteophytes)
px with OA usually present to GP with ….
pain + loss of mobility in joints
whats an Osteophyte?
bony spurs visible in Xray
what would you expect to see in the hands of someone with OA?
bony nodules
What are the risk factors for osteoarthritis?
- older age
- women (menopause + estrogen levels)
- obesity
- smoking
- hypermobility (sports/traumatic injury)
- osteoporosis
What parts of the joint does osteoarthritis affect? 4
- cartilage
- subchondral bone
- synovium
- skeletal muscle
whole joint, not just cartilage
How does osteoarthritis affect the cartilage within the joint?
causes fibrillation and degradation
How does osteoarthritis affect the skeletal muscle on a joint?
causes muscle weakness and atrophy
How does osteoarthritis affect the subchondral bone within the joint?
causes:
- trabecular thickening
- under-mineralisation
How does osteoarthritis affect the synovium within the joint?
causes thickening and inflammation
What is the function of articular cartilage?
absorb load on the joint
Where is the articular cartilage located within the knee and what are they called?
- end of femur: femoral condyle cartilage
- end of tibia: tibial plataeu cartilage
What is the names of the cartilage located in the hip joint?
- femoral head cartilage
- hip socket cartilage
how does cartilage look in normal joint?
white, glossy
what are the cells of the articular cartilage?
chrondocytes
what do chondrocytes produce?
proteins that form an extracellular matrix.
outline the extracellular matrix formed by chondrocytes
network of type 2 collagen fibres
proteoglycans with GAG side chains
- bottle brush appearance
- trap water which gives load absorbing properties
- non collangenous proteins such as fibronectin
60-80% of cartilage is made up of what?
water
articular cartilage structure typically acellular and doesnt have…
blood supply/ nerves/ lymphatic system
not well vascularised
explain what happens to the articular cartilage when its absorbs a load?
load applied to joint
cartilage compressed water
repulsive forces from proteoglycans within ECM balance applied load, load removed,
load removed
proteoglycans rehydrate and restore cartilage shape
what proteoglycan in particular is important in the absorbance of load, by cartilage?
aggrecan in ECM maintaining compressive + repulasive force
what does cartilage protect bone from?
shock impact
cartilage proteoglycan histological stains used?
H&E
safranin O (red)
Toluidine Blue
upon inflammatory stimuli chrondocytes proliferate and undergo what?
hypertrophy
upon inflammatory stimuli chrondocytes undergo hypertrophy. What happens to cartilage when RUNX2 and hedgehog (TFs) are induced?
promote more hypertrophy,
- reduced matrix synthesis due to reduced type 2 collagen and aggrecan proteoglycan
- increased matrix proteases MMPs and ADAMTS
role of TFs RUNX2 and Hedgehog?
regulatory TFs, push chondrocytes to become more hypertrophic + pro-inflamm and start excreting matrix proteases
name 2 matrix catabolic proteases excreted in process of chondrocyte hypertrophy
(cartilage degradation) + their role
MMPs degrade type 2 collagen fibres
ADAMTS4 and ADAMTS5 degrade aggrecan proteoglycans
chondrocytes normally inactive + maintain tissue homeostasis. what happens in OA?
get big in inflammation + proliferate more
what is OA subchondral bone described as ? and what does it look like?
sclerotic
thickened struc (but undermineralised), seen in Micro CT scans
what is the Goldner stain used to observe in OA?
un-mineralised bone (subchondral)
yellow= cartilage
and none= lack of it. OA
how is presence of abnormal type1/ alpha 1 collagen linked to brittle bone?
increased alpha1 collagen expression -> HOMOtrimer (normal type1 collagen = hetrotrimer) formn -> kinking in struc = brittle bone
synovitis is an early feature of OA? What is this?
inflammation of the synovium
how can synovitis be detected early on?
MRI,
ultrasound,
histochemical analysis of synovial tissue and increased amounts of pro inflammatory cytokines in joint fluid
how would synovium appear in OA?
thicker, inflamed
and more pro inflamm cytokines picked up as bright white legions in MRI/ radiograph
2 things that together drive both joint damage and joint pain?
synovitis and inappropriate activity of fibroblast cells
synovial inflamm cytokines promote what?
cartilage degradation and further synovial inflammation
how does synovitis + fibroblast cells drive joint pain?
synovial inflamm cytokines promote cartilage degradation and further synovial inflammation
inflamm OA synovial fluid cytokines sensitises joint nociceptors
sensitised nociceptors promote pain signalling -> dorsal horn
drug class for the 1st line treatment of OA?
topical or oral NSAIDS
name 2 drugs that would be appropriate for the 1st line treatment of OA OTC to provide short term pain relief?
aspirin and ibuprofen
MoA of aspirin/ ibuprofen in the treatment of OA?
inhibit COX enzymes, reduce prostaglandins as PEG2 promotes pain in OA
why are NSAIDs not appropriate for the long term treatment of OA?
non selective = GI issues, peforation, ulceration and bleeding, reduces protective prostanoids in GIT
main component of ibuprofen/ nurofen?
arachidonic acid
why might celecoxib and similar drugs be better than ibuprofen for pain management in OA?
cox 2 selective so reduced inflammation and more gastro protective
why are cox 2 selective inhibitors not recommended for routine use except those at high risk of GI issues?
associated with increased CV risk.
caused by increase in balance between TXA2 and PGI2 -> vasoconstriction +platelet aggregation
how do selective COX2 inhibitors –> CV events? SE
p364 pics!
PGs and TXA2 maintain vasoconstriction + dilation of BV, normally in a fine balance.
drugs tip scales so get:
↑ TXA2
↑ vasoconstriction
↑ platelet aggregation
↑ risk of CV events
name an adjunct therapy that is appropriate for patients with knee OA?
glucocorticoid (GCC) intraarticular injections
although GCC injections relieve pain, why are they short lived?
frequent injections accelerate cartilage damage
outline how excess glucocorticoids can cause bone resorption and have the opposite desired effect?
- ↑RANKL ↓OPG secretion from osteoblasts
-> activation of osteoclasts - chronic ↑PTH and ↓BMP2
- osteoblast proliferation ↓
- osteocyte apoptosis ↑
- ↓bone sensing + initiation of bone remodelling
What does BMP2 do?
acts on osteoblasts to form bone
how many more times at risk are obese people of developing osteoarthritis?
3-5
what fruit shape is associated with excess fat around the belly region and which fruit shape is associated with excess fat around the hip and thighs?
apple and pear
is a high WHR (>0.9) and a low WHR (<0.85) associated with increased risk of OA?
high whr
outline some of the reasons why obesity a risk factor for OA?
- traumatic loading can induce cartilage damage
- degredation fragments like fibronectin promote more inflammation
- high whr suggests metabolic syndrome related effect
- adipose tissue is endocrine tissue and secretes adipokines
- obese tissue secretes more pro inflammatory cytokines which affect the tissue joints
is which areas is visfatin highly expressed and what does it promote?
areas of cartilage damage,
promotes induction of MMPs in cartilage
___ ____ drives an abnormal Type 1 collagen a1/a2 bone phenotype change
adipokine resistin
what type of fibroblasts are more inflamm + more proliferative?
obese
whats been recently identified as central mediators of the inflamm repsonse?
LncRNAs
expression induced by obesity-associated pro-inflamm cytokines/adipokines
what LncRNA mediates inflamm obese Synovial Fibroblast Phenotype ()
MALAT1
what identifies distinct fibroblast cell subset populations (drivers of certain phenotypes) associated w joint pain?
single cell (RNA) sequencing
name a gene present in fibroblasts at sites of joint pain that is also a promotor of nerve cell growth?
NRN1
true or false: pain associated fibroblasts do not promote the survival and growth of neurones
false
Summarise the treatment options for OA.
no disease modifying therapeutics, only symptom treating drugs:
- NSAIDs, COX2 inhibitors
- intra-articular glucocorticoid injections
obesity + OA what 2 processes can adipokines drive?
cartilage damage
sclerotic bone formation
