ic10 msk pathophysiology

Question 1

different bone marrows and their function

Answer 1

red: hematopoeisis
yellow: fatty connection tissue used in times of starvation

Question 2

skeleton function

Answer 2

storage of calcium and phosphate to regulate mineral balance in blood stream.

form support stability movement

Question 3

muscle characteristics

Answer 3

connected to bones, arranged in opposing groups around joints = keep bones in place, plays a role in movement

muscles are innervated - CNS = contraction

Question 4

what is a tendon

Answer 4

tough flexible band made of fibous connective tissue
connect muscle to bones.

Question 5

what are DAMPS

Answer 5

damage-associated molecular patterns
e.g.
ATP, S100, HMGB1,
IL-1alpha (most common),
HSP70 (circulation)
histones, PRR…

released during various types of cell death/stressed cells

recognised by tissue macrophages = release inflammatory cytokines

High mobility group box 1 protein, Heat shock protein 70

Question 6

brief overview of initial immune response to tissue injury

Answer 6

neutrophils recruited first (hours; by CXCL8) > monocytes/macrophages (1-3days; by CCL2) > T cells (1-2 weeks)….

Question 7

what are the inflammatory cytokines and the following mechanism

Answer 7

IL1, IL6
IFN-Y,
TNF alpha
IL17
….
activates inflammatory macrophages (M(IFN-y)) = differentiate to tissue repair macrophages

Question 8

why is tissue healing impaired/has scarring or fibrosis occurred during the immune response

Answer 8

inflammatory macrophage M(IFN-y) stimulate T cells (Th and CD8+) in positive. feedback loop
= inhibit tissue stem cells

M(IFN-y) may also differentiate to pro-fibrotic macrophage M(IL-4)-like to increase ECM protein deposition and subsequent fibrosis (scarring)

also release TGF-beta and PDGF to cause differentiation of pericytes to scar forming myofibroblasts

Question 9

what is secreted for fibrosis

Answer 9

profibrotic MMP TIMPS

Question 10

adaptive immune cytokines

Answer 10

IL2, IL6, IL12, IL23, TGF beta (differentiate CD4+ helper cells)

Question 11

immunosuppressive/regulatory inflammatory cytokines

Answer 11

IL10
TGF beta
IL 7
GM-CSF

Question 12

overview of tissue regeneration

Answer 12

M(IL10)-like activate regulatory T helper cells by secreting anti-inflammatory cytokines like IL10
which inturn secrete growth factors PDGF, VEGF, IGF-1…

Question 13

OA description

Answer 13

caused by the overuse of joints (including physical or sports injury, weight bearing) = deterioration

Question 14

OA pathophysiology

Answer 14

articular cartilage damage = chondrocyte activity to remove and repair damage (become hypertrophic) = aberrant chondrocytes = more breakdown

cartilage loss (due to MMP, vasoactive peptide release from subchondral bone = collagen breakdown) and apoptosis of chondrocytes

STIMULATE PATHOLOGIC CHANGE (release of inflammatory cytokines)
= form fibrillation in cartilage + cartilage shards
= subchondral bones rub against each other + sclerosis, microfracture, osteophyte formation

Question 15

how do chondrocytes cause tissue degeneration in OA

Answer 15

chondrocytes release DAMPS that bind to PRR = release of cytokines eg IL1, IL6, TNF-alpha= hypertrophy = NFKB activation, upregulation of NO, PGE2, activation of complement/adaptive immune system (B, T cells) = progressive synovitis = effusion, synovial thickening

Question 16

what causes pain in RA

Answer 16

pain caused by distension of the synovial capsule

activation of nociceptive nerve endings

Question 17

non-medical tx for OA

Answer 17

physical, occupational therapy
transcutaneous electrical nerve stimulation (TENS)
synovectomy
tendon repair
realigning bones
joint fusion
total joint replacement

Question 18

pathophysiology of rA

Answer 18

genetic predisposition + immunologic trigger
= t cell mediated immune response
= inflammation
= recruitment of inflammatory cells
= release of protease, prostaglandins,
= destruction of articular cartilage, underlying bone

inflmm also associated w angiogenesis in synovium = synovial cell proliferation/activation = pannus activation

ALSO, release of inflammatory cytokines = activation of osteoclasts = bone breakdown

Question 19

gout causes

Answer 19

1) overproduction of uric acid
= primary: inborn errors of metabolism
= secondary: conditions increasing cell turnover and purine generation

2) underexcretion of uric acid

Question 20

gout patho

Answer 20

glutamine + PRPP = NUCLEIC ACID in body tissues
breaks down to guanine, adenine, then hypoxanthine
(xanthine oxidase)
= xanthine = uric acid

Question 21

role of PRPP

Answer 21

phosphorobosyl pyrophosphate
salvage pathway

reuse guanine and hypoxanthine to form nucleic acids

Question 22

how do MSU crystals cause pain and inflammation

Answer 22

MSU crystals = formation and activation of inflammasome complexes
= Caspase-1 activation
= IL-1 beta (through pyrotopic pores)
= DAMPS immune response activation (on endothelial cells, synoviocytes)
= increase cytokine, chemokines
= activate inflammatory cascade, neutorphil influx

*inflammasome also causes formation of ROS via potassium efflux

Question 23

how are inflammasomes produced

Answer 23

stimulation of TLR (receptors) causes production of NF-KB transcription factors = formation of inflammasome components.

Question 24

what is anakinra

Answer 24

recombinant IL1- RA
4-6 hours t1/2
SC administration

canakinumab is human anti-IL-1beta monoclonal antibody

Question 25

what are osteoblasts

Answer 25

derived from mesenchymal stem cells for bone matrix synthesis and mineralisation

Question 26

what are osteocytes

Answer 26

osteoblasts that become incorporate into the newly formed osteoid = calcified bone 1) respond to changes in physical forces upon bone 2) transduce message to cells on the bone surface = initiate formation/resorption

Question 27

what are osteoclasts

Answer 27

large multinucleated cells attached to bone surface/ derived from hematopoietic lineage resorption of mineralised tissue

Question 28

what is the process of bone remodelling and renewal?

Answer 28

1) activation and resorption - preosteoclast stimulated = differentiate (cytokines, growth factors) = mature osteoclast = resorption 2) reversal - end of resorption 3) formation - osteoblast synthesis new bone matrix 4) quiescence - osteoblast become resting bone lining cells

Question 29

how do GC cause 2º osteoporosis

Answer 29

1) decrease differentiation of osteoblast. 2) increase death of osteoblast and osteocytes.