ic10 msk pathophysiology Flashcards
different bone marrows and their function
red: hematopoeisis
yellow: fatty connection tissue used in times of starvation
skeleton function
storage of calcium and phosphate to regulate mineral balance in blood stream.
form support stability movement
muscle characteristics
connected to bones, arranged in opposing groups around joints = keep bones in place, plays a role in movement
muscles are innervated - CNS = contraction
what is a tendon
tough flexible band made of fibous connective tissue
connect muscle to bones.
what are DAMPS
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
brief overview of initial immune response to tissue injury
neutrophils recruited first (hours; by CXCL8) > monocytes/macrophages (1-3days; by CCL2) > T cells (1-2 weeks)….
what are the inflammatory cytokines and the following mechanism
IL1, IL6
IFN-Y,
TNF alpha
IL17
….
activates inflammatory macrophages (M(IFN-y)) = differentiate to tissue repair macrophages
why is tissue healing impaired/has scarring or fibrosis occurred during the immune response
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
what is secreted for fibrosis
profibrotic MMP TIMPS
adaptive immune cytokines
IL2, IL6, IL12, IL23, TGF beta (differentiate CD4+ helper cells)
immunosuppressive/regulatory inflammatory cytokines
IL10
TGF beta
IL 7
GM-CSF
overview of tissue regeneration
M(IL10)-like activate regulatory T helper cells by secreting anti-inflammatory cytokines like IL10
which inturn secrete growth factors PDGF, VEGF, IGF-1…
OA description
caused by the overuse of joints (including physical or sports injury, weight bearing) = deterioration
OA pathophysiology
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
how do chondrocytes cause tissue degeneration in OA
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
what causes pain in RA
pain caused by distension of the synovial capsule
activation of nociceptive nerve endings
non-medical tx for OA
physical, occupational therapy
transcutaneous electrical nerve stimulation (TENS)
synovectomy
tendon repair
realigning bones
joint fusion
total joint replacement
pathophysiology of rA
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
gout causes
1) overproduction of uric acid
= primary: inborn errors of metabolism
= secondary: conditions increasing cell turnover and purine generation
2) underexcretion of uric acid
gout patho
glutamine + PRPP = NUCLEIC ACID in body tissues
breaks down to guanine, adenine, then hypoxanthine
(xanthine oxidase)
= xanthine = uric acid
role of PRPP
phosphorobosyl pyrophosphate
salvage pathway
reuse guanine and hypoxanthine to form nucleic acids
how do MSU crystals cause pain and inflammation
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
how are inflammasomes produced
stimulation of TLR (receptors) causes production of NF-KB transcription factors = formation of inflammasome components.
what is anakinra
recombinant IL1- RA
4-6 hours t1/2
SC administration
canakinumab is human anti-IL-1beta monoclonal antibody
what are osteoblasts
derived from mesenchymal stem cells
for bone matrix synthesis and mineralisation
what are osteocytes
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
what are osteoclasts
large multinucleated cells attached to bone surface/
derived from hematopoietic lineage
resorption of mineralised tissue
what is the process of bone remodelling and renewal?
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
how do GC cause 2º osteoporosis
1) decrease differentiation of osteoblast.
2) increase death of osteoblast and osteocytes.
