Osteoarthritis Flashcards
(12 cards)
Osteoarthritis
- chronic degenerative condition of synovial joints
- symptoms: stiffness, swelling, crepitus, muscle weakness, instability, fatigue and pain
- risk factors: age, female, weight, injury
Osteoarthritis pathogenesis
- different patients likely have different predominant mechanisms
- e.g. cartilage vs synovitis phenotypes
3 core characteristics
- cartilage dysfunction
- synovitis
- bone remodelling
Cartilage dsyfunction
- articular cartilage is avascular and largely reliant on glycolysis (aerobic and anaerobic)
- shifts to anaerobic in osteoarthritis
- hypoxia and proinflammatory mediators impair mitochondrial function
- increased ROS = nutrient stress = lactate/acidic environment
- reduced anabolism and increased catabolism = cartilage erosion and fissure
Cartilage dysfunction and chondrocytes
- chondrocytes attempt repair but are dysregulated so generate proinflammatory mediators and ECM breakdown products
- monosodium iodoacetate model of OA = glyceraldehyde-3-phosphate inhibition = glycolysis is disrupted
- cartilage proteoglycan aggregate can undergo cleavage by matrix metalloproteases to produce 32-mer peptide
- 32-mer peptide = increases chondrocyte proinflammatory gene expression
- and TLR2-dependent DRG neurone excitation
Osteoarthritis and Nav1.7
- the worse the damage of OA is, the more Nav1.7 that is present
- Nav1.7 KO in chondrocytes = reduced mice OA pathogenesis and pain
- inhibiting Nav1.7 releases protective factors
Synovitis
- inflammation within the synovium
- synovitis correlates with the baseline knee pressure pain threshold
- neither effusion nor bone marrow lesions correlate with baseline or change in PPT
- synovial tissue contains different cell types
- fibroblast-like synoviocytes (FLS) hyperplasia and proinflammatory mediator secretion are key
- numerous immune cells contribute to OA pathogenesis e.g. macrophage, mast cells and some T cells
Bone remodelling
- bone marrow lesions
- breaching of the tidemark
- and subchondral bone marrow lesions innervated by sensory neurones
- osteophytes = dysregulation of bone growth
OA pain mechanisms
- changes in CNS processing but peripheral drivers are key
- OA synovial fluid contains inflammatory mediators e.g. NGF and TNFalpha
- does OA-SF modulate neuronal function?
- OA-SF decreased current required to induce AP firing
- compared to control medium; would need to test healthy SF too!
- healthy SF also decreased rheobase
- lots of different cell types infiltrate OA joints
- FLS are present in all individuals, but different subtypes
- conditioned medium from TNF stimulated FLS = increased probability of spontaneous firing
- co-culture of TNF-FLS medium and knee-innervating neurones = hyperexcitability
- increased proton concentrations in many joint conditions
OA pain mechanisms - GPR65
- GPR65 expressed by FLS, macrophages
- selective GPR65 agonist = BTB
- intra-articular BTB = swelling and pain
- knee-innervating neurones from BTB injected are hyperexcitable
- BTB stimulates FLS cytokine release during sensitisation
- GPR65 KO mice = no effect of BTB (only acts on GPR65)
- BTB has a dose-dependent response
Cell-cell interactions
- when culturing DRG, other cell types e.g. macrophages are present
- magnetic activated cell sorting uses Abs to remove non-neuronal contamination
- increased granulocyte macrophage colony stimulating factor (GM-CSF) in OA
- GM-CSF fails to significantly alter gene expression in DRG
cell-cell interaction pathway:
GM-CSF –> macrophages –> DRG neurone hyperexcitability
Neoinnervation
- as OA pathogenesis progresses, neoinnervation occurs
- increased neuronal innervation of changes in those with knee OA pain
- inducing OA in rats increases pain behaviours, prevented by treatment with TrkA inhibitor
TrkA inhibition prevents neuronal innervation of channels in rats with OA properties of subchondral neurones
- Nav1.8 increased in L3-5 DRG after ACLT
- Nav1.8 positive increased in subchondral nerve fibres
- ACLT induces hyperalgesia
Neoinnervation - regulation of Nav1.8
what regulates Nav1.8 expression?
- increased COX2 positive osetoblasts and increased PGE2, decreased Na1.8 positive subchondral
- same if KO EP4R (which PGE2 works through)
- killing of Nav1.8 positive nerves does not impact OA progression
