LOCO EOYS1 Flashcards
Label A & B [2]
A: EphB4 (receptor on osteoblast)
B: EphrinB2 (ligand on osteoclast)
Forward signaling through EphB4 stimulates
osteoblast
osteoprogrenitors
osteoclast
osteoid
osteocyte
osteoblast and bone formation
When ephrinB2 and ephB4 bind, which is switched off?
osteoblast
osteoprogrenitors
osteoclast
osteoid
osteocyte
osteoclast
Which of the following have a receptor for PTH?
What effect does this cause? [1]
osteoblast
osteoprogrenitors
osteoclast
osteoid
osteocyte
osteoblast: causes production of RANKL - causes more osteoclast activity & number
which cell type makes OPG?
What is the function of OPG?
osteoblast
osteoprogrenitors
osteoclast
osteoid
osteocyte
osteoblast: inhibits osteoclast activity
Describe action of increased PTH [3]
Low Ca2+ levels stimulates PTH secretion
PTH promotes:
* Ca2+ reabsorption from kidney and PO4 excretion at the kidney
- Osteoblasts have receptor for PTH, osteoblasts produce RANKL, osteoclasts and their precursors have RANK receptor; increases number and activity of osteoclasts
- Synthesis of 1,25-dihydroxyvitamin D (1,25 (OH)2 vitamin D3)
Which receptor does FGF23 bind to? [1]
What is the effect of FGF23 activation? [3]
FGF23 produced by osteoclasts / blasts, targets the kidney:
FGF23 binds to Klotho
Action:
* Causes reductions in serum phosphate and 1,25(OH)2D levels
* Reduces PTH secretion
Name 3 pro-inflammatory RANKL inducers [3]
Name 1 RANKL inhibitor [1]
Inducers
TNF-a
IL-1
Prostaglandin E2
Inhibitors
Oestrogen
Describe the physiological effects of calcitonin [3]
- inhibits osteoclast differentiation and activity
- increases Ca2+ excretion from kidney
- Inhibits Ca2+ absorption by intestines
Describe effect of oestrogen at the:
Gut [1]
Bone [1]
Gut - increased Ca2+ absorption
Bone - decreased re-absorption (inhibit osteoclasts)
Describe the effect of adding progesterone ceram to osteoporosis therapy [1]
increases bone density by around 10% in 1st 6 months to rate of 3-5% annually stabilises at levels of 35 year old
Describe the action of FSH on osteoclasts [1]
Describe the action of FSH on IL-1. TNF and IL6 [1]
Direct action on osteoclasts upregulates RANK
Indirect action on monocytes to secrete IL1, TNF and IL6
Ca2+ homeostasis
Describe effect of glucocorticoids at the:
Gut [1]
Bone [1]
Gut - decrease Ca2+ absorption
Bone - increased re-absorption/decreased formation
Describe the effect of 1,25(OH)2D acting on vitamin D receptor:
- During normal levels of 1,25(OH)2D
- During elevated levels of 1,25(OH)2D
Normal levels of 1,25(OH)2D act via the VDR (Vitamin D Receptor) in mature osteoblasts to decrease the ratio of RANKL/OPG and reduce osteoclastic bone resorption. As well, 1,25(OH)2D action via the VDR in mature osteoblasts increases the bone formation rate (BFR).
Increased levels of 1,25(OH)2D acting via the VDR in less mature osteoblasts may increase RANKL/OPG, stimulate osteoclastic bone resorption, and reduce trabecular bone
The action of high levels of 1,25(OH)2D in mature osteoblasts and osteocytes can increase local and systemic inhibitors of osseous mineralization and decrease mineralization of bone leading to osteomalacia
Prolonged corticosteroid treatment leads to which disease? [1]
osteoporosis
Which cell is ephB4 receptor found on
osteoblast
osteoprogrenitors
osteoclast
osteoid
osteocyte
Which cell is ephB4 receptor found on
osteoblast
osteoprogrenitors
osteoclast
osteoid
osteocyte
Osteoblasts produce RANKL & OPG. State what their roles are in bone signalling [2]
RANKL:
* binds to RANK and stimulates osteoclastic bone resorption
osteoprotegerin (OPG)
* inhibits osteoclast differentiation, fusion, and activation
* protects bone from excessive resorption by binding to RANKL and preventing it from binding to RANK.
State 3 molecules that inhibit bone resorption
transforming growth factor beta (TGF beta) (via increase in OPG)
interleukin 10 (IL-10)
osteoprotegerin (OPG)
calcitonin
* interacts directly with the osteoclast via cell-surface receptors
estrogen (via decrease in RANKL)
* stimulates bone production (anabolic) and prevents resorption
* inhibits activation of adenylyl cyclase
Label A-E
A: calcified cartilage
B: chondrocytes
C: tide line
D: hyaline cartilage
E: articular surface
Hyaline cartilage: non-calcified
Deeper layers of cartilage are calcified: darker
Seperated via a tide mark
Articular cartilage
Label A-E
A: tangenitial layer
B: transitional layer
C: radial layer
D: calcified cartilage
E: bone
Which cells being damaged in OA causes the inflammatory response to occur? [1]
The release of which molecules occurs as a result of this? [2]
What happens to the synovial joint as a result of this? [2]
Describe the MoA for the release of AN the role of proinflammatory cytokines in the pathophysiology of OA [3]
Once the chondrocytes become damaged, they release pro-inflammatory cytokines which causes inflammatory response in the rest of the joint:
- increase the production of matrix metalloproteinases and ADAMT-4
- reduce aggrecan production and type 2 collagen production
- overall cartilage degradation
- Local inflammation: IL-1, IL-6, TNF
Describe key changes in pathology of OA
- Repetitive excess mechanical loading is what leads to stress-induced signals in the articular cartilage
- Chondrocyte cloning and hypertrophy
- tidemark duplication, followed by osteophyte formation, bone microfractures, angiogenesis
Name a gene that is known to contribute to OA pathogensis [1]
What is the effect of losing this gene [3]
HMGB2: high mobility group protein 2 (chromatin protein)
Loss of HMGB2, leads to superficial zone cell death, loss of progenitor cells, and reduced synthesis of ECM components
Macroscopically articular cartilage goes through 3 phases of degeneration. What are they? [3]
Fibrillation: rougher with frilly edges, compared to the usual nice and smooth appearance
Erosion and cracking: these cracks bigger and bigger due to the hydronic action in the joint
Eburnation:
* Complete loss of cartilage
* Completely exposed bone becomes polished
Microscopically what happens in pathogenesis of OA? [3]
Chondrocyte necrosis - more in superficial layers. Dead cells not removed: ECM contamination
Focal clumps or clones of chondrocytes
* Increased local proliferation
* Large Isogenic clusters
* (The middle zone normally contains evenly spread out layers of chondrocytes, yet in osteoarthritis there are isogenic clusters/focal clumps of chondrocytes due to increased local proliferation where they group together in areas)
Change from type II to type I cartilage
* Reduces thickness of articular cartilage & Duplicated tidemark
What is happening in this slide of OA? [1]
Conversion of type II to type I collagen
Describe final stage; of OA impacting the subchondral bone
As articular cartilage is eroded, the underlying bone is exposed:
* There is microfractures of the trabeculae,
* increased osteoblastic activity and new bone formation
* resulting in subchondral sclerosis
* The surface also undergoes focal pressure necrosis, which leads to subarticular cysts forming.
* There is vascular engorgement, which slows blood flow, and there is bone marrow oedema.
OA
What change has undertaken at A [1]?
Eburnation of cartilage: complete loss of cartilage, exposing bone
OA
What change has undergone at the A? [1]
Eburnation of cartilage: complete loss of cartilage, exposing bone
OA
Name the change that the arrow is pointing to [1]
Fibrillation: saw tooth surface irregularity of cartilage
OA
Name the change that the arrow is pointing to [1]
A-Fibrillation of the articular cartilage (arrow)
OA
Name the change that the arrow is pointing to [1]
Eburnation of articular cartilage
Describe the pathophysiology of RA [4]
RA is primarily a synovial disease and synovitis (inflammation of the synovial lining) occurs when chemoattractants produced in the joint recruit circulating inflammatory cells
- Over-production of TNF-alpha leads to synovitis
and joint destruction
Type A synoviocytes proliferate:
* increase in number of macrophages
* Early RA: Subintima normal
Infiltration of inflammatory cells:
* Synovial fluid: neutrophils
* Subintima: lymphocytes (CD4 T helpers; dendritic cells; macrophages)
* Both become thicker & more dense
Proliferation of fibroblasts in subinitima causing thickening
Generation of new synovial blood vessels is induced by angiogenic cytokines and activated endothelial cells produce adhesion molecules which FORCE LEUCOCYTES into the synovium - where they can trigger inflammation
The synovium proliferates and grows out over the surface of the cartilage (past the joint margins), producing a tumour-like mass called ‘pannus’
- This pannus of inflamed synovium DAMAGES the underlying cartilage by blocking its normal route for nutrition and by direct effects of cytokines on the chondrocytes
The cartilage becomes thin and the underlying bone exposed
- The pannus DESTROYS the articular cartilage and subchondral bone
resulting in bony erosions
What is a pannus? [1]
Where are pannus created? [1]
What can be the effect of pannus creation ? [2]
Villi like projections caused by proliferation of SF and subintima:
Created at the small microenvironment of bone-cartilage junction
. Concentration of pro-inflammatory cytokines causes increase in osteoclasts and thickening of lining and subintima
Causes synovial membrane to grow over and erode articular cartilage
Describe mechanism of how pannus causes bony erosions [3]
- This pannus of inflamed synovium DAMAGES the underlying cartilage by blocking its normal route for nutrition and by direct effects of cytokines on the chondrocytes
- The cartilage becomes thin and the underlying bone exposed
- The pannus DESTROYS the articular cartilage and subchondral bone
resulting in bony erosions
From PBL answers:
Pannus
Grows over and into the articular cartilage
Produces cytokines that attack cartilage and break it down
Cytokines induce synovial fibroblasts to differentiate into osteoclasts to breakdown peri-articular bone
What is the overall net effect of RA on osteoblasts? [1]
Describe the cytokines that drive this effect of osteoblasts to occur [3]
Osteoblasts are switched off:
- (TNF-a, IL-1 & IL-6 produce RANKL to turn on osteoclasts)
- AND
- Induced expression of DKK-1: induces sclerostin (reduces osteoblastic bone formation)
Describe the first [3] and second [3] step that occurs in PAD-dependent differentiation and maturation of osteoclasts
1st step:
* Gradual increase in cell citrullination occurs as a consequence of increased PAD enzyme activity in a calcium-rich microenvironment.
* ACPAs present in the circulation can reach and bind to maturing osteoclasts in the bone marrow, leading to an increase in OC activity and
* consecutive bone resorption through a IL-8 dependent autocrine loop.
Second step:
* IL-8 will reach the joint and initiate the chemoattraction and migration of inflammatory cells, particularly neutrophils.
* Neutrophil extracellular traps are released by neutrophils in the presence of ACPAs,
* This further contributes to the joint inflammation and local accumulation of other inflammatory cells, such as macrophages, and activation of synovial fibroblasts
State and explain the two different subclasses of RA [2]
- Which populations are they more common in? [1]
- Which type of infection are each more common with? [1]
- Which HLA types are more risky for each?
Describe the factors that cause each [4] & [3]
Seropostive (ACPA positive): more common
* Smokers
* Bacterial infections
* HLA DRB1 alleles
* PTPN22
Seronegative (ACPA negative)
* Viral Infections:EBV, cytomegalovirus
* HLA-DR risk alleles
* Contribution of HLA alleles much lower and different (HLA-DR3)
* IRF5 = human interferon regulatory factor-5: Mediates virus induced immune response
Explain the process of NETosis in the initiation of RA [3]
- Ca2+ dependent
- Bacterial stimulus attracts neutrophils
- Neutrophils release NET fibres (made from DNA) that entrap microorganism: forms a scaffold for enzymes, peptides etc. High concentrations kill microbes.
- Results in neutrophils dying / suicidal NETosis
RA
Label A & B
A: swan neck deformity
B: Boutonniere deformity
