Bone & Fat Flashcards
What is the role of DKK-1?
DKK-1 is negative regulator of WNT/beta catenin pathway; binding to a Wnt receptor
(TNFalpha will promote it) blocks Wnt activation of preosteoblast to mature osteoblast - this will bind to receptor for Wnt and inhibit Wnt action on maturation of osteoblast. in mature osteoblast
What is the role of Osteoprotegerin?
OPG: Osteoprotegerin; inhibits RANKL which is essential for formation of osteoclasts
Osteoprotegerin (OPG) protects the skeleton from excessive bone resorption by binding to RANKL and preventing it from binding to its receptor, RANK
OPG (osteoprotegerin) mainly from OB is a decoy soluble receptor
What do mesenchymal stem cells give rise to? Hematopoietic stem cells?
mesenchymal SC- give rise to pre-OB and chondrocyte
What does Wnt do?
Wnt suppress osteoclast-mediated bone resorption by down regulate expression of RANKL, and upregulation of OPG
urges MSC toward preosteoblast… and inhibits other lineages like chondrocytes
What family are RANK and RANKL members of?
TNF superfamily
What does bone mass and skeletal integrity depend upon?
Thus, RANKL/OPG ratio is an important determinant of bone mass and skeletal integrity
The ratio between OPG and RANKL determines bone formation
Where is RANK expressed?
What is RANKL?
RANK expressed on pre-OC and OC: receptor
RANKL is the cytokine
What do OB release?
OB releases M-CSF that promotes OC survival and proliferation
Which cells can express RANKL?
RANKL can be expressed by many innate and adaptive immune cells, including neutrophils, monocytes, DC, T and B cells
What cytokines induce RANKL?
Which will suppress/reduce expression of RANKL?
Proinflammatory cytokines IL1,IL6, IL8, TNFα and especially Th17 induce RANKL and promote OC differentiation
Th2 - IL4, IL10, IL13 will reduce expression
What effect will sex hormones have?
Sex hormones: maintain bone homeostasis
Describe how T cells are involved in bone modeling particularly in a dominant Th1 or Th17 response.
When might Th17 response be inhibited?
A dominant Th1 response in and around bone is associated with INFγ and activates macrophages. Result: pro-clastogenic and bone resorption
TH17 cells, if dominant, are potent OC activators
A normal Th1 or TH2 response or balanced Th1/Th2 responses would strongly inhibit IL 17. Result: a good thing
In what clinical scenario might you see increased IL23? What would this indicate? Describe the Th response and mechanisms.
Rheumatoid Arthritis
Increased IL23-stimulus unknown- appears in high levels in synovium of a joint
Th17 cells infiltrate the synovium
IL17 activates neighboring OC and they proliferate
The RANK/RANKL/OPG balance is pro-bone loss and causes bone erosions and loss of joint function
What is Denosumab? Describe its action.
Denosumab is an human monoclonal antibody for treatment of osteoporosis.
is good at binding and soaking up the RANKL …by doing that you push balance back toward OB rather than OC.
Blocking RANKL with a monoclonal antibody (Denosumab) can lead to decreased bone loss
What is Pannus?
Pannus is inflammatory synovial tissue: source of cytokines that mediate bone loss.
(RA?)
Slide 16
Describe role of estrogen in pre and post menopausal women.
Premenopausal state: estrogen promotes normal OB & OC function
Post menopausal state: OPG/RANKL balance is altered
Blocking RANKL with a monoclonal antibody (Denosumab) can lead to decreased bone loss
Does an inflammatory state increase or decrease with an increase in adipose tissue?
high level of adipose tissue- more toward inflammatory state
Obesity is firmly linked to major adverse health outcomes, especially DM-2 and insulin resistance
Adipose tissue is the largest endocrine organ that produces a wide array of hormones that act like cytokines and vice-versa
Any stimulus that increases inflammation in adipose tissue is a bad thing
Can white adipose tissue be classified as an endocrine organ?
Super endocrine organ and critical for homeostasis
Produces hormones, chemokines and cytokines
Regulates energy storage and expenditure, body mass and immune responses
Composed of pre-adipocytes, adipocytes, stromal/vascular cells and macrophages
What are M1 and M2? Describe roles. Where are they?
Describe cytokines released and which Th response for each.
WAT Communicators: Macrophages
M1 is pro-inflammatory
M2 is anti-inflammatory
M1: Th1 response, IL1, IL6, IL8, and TNFa
M2: Th2, IL4, IL10, IL13
What are Osteopontin and Resistin? Where are they? What are they? Describe their roles/what they produce.
These are Macrophage-Derived Cytokines in WAT
Osteopontin: A pro-inflammatory and a potent chemotactic signal for monocytes and macrophages
Resistin: antagonist of adiponectin
Produce the usual suspects: IL1,6,8, TNFα
Adiponectin is produced from adipocytes and has anti-inflammatory function – insulin sensitizer
Describe action of adiponectin and resistin.
Adiponectin is produced from adipocytes and has anti-inflammatory function – insulin sensitizer
Resistin: antagonist of adiponectin
Adipocytes of WAT produce adipocytokines that act like cytokines & hormones and have broad spectrum effects
Describe the effects (pro-inflammatory or anti-inflammatory)
Leptin
Adiponectin
Visfatin
Describe macrophage inhibitory factor cytokine.
Leptin is pro-inflammatory
Adiponectin is anti-inflammatory
Macrophage inhibitory factor cytokine is TNF- like but promotes adiponectin release
Visfatin is pro-inflammatory and pro angiogenic
Most abundant are leptin and adiponectin
Leptin: appetite control, CNS
Adiponectin: insulin sentisizer
What cytokine is an insulin sensitizer? Where is it produced? Describe its function.
Adiponectin is produced from adipocytes and has anti-inflammatory function – insulin sensitizer
How can expanding fat in adipocytes make WAT pro-inflammatory?
Expanding fat in adipocytes triggers a very dangerous signaling program that makes WAT very pro-inflammatory by recruiting a large number of monocytes and macrophages into it
The portal vein carries the problem into the liver and (probably) also into atheromatous plaques
How does adipose tissue differ in lean vs obese individuals?
Describe levels of Tregs.
How will Wnt5a, SFRP5, adiponectin, MAC and TNFa change in obese individuals?
Macrophages regulate adipogenesis through WNT5a and TNF-like cytokines.
SFRP5: Secreted Frizzled-Related Protein 5; Frizzled is membrane receptor for WNT proteins. SFPR5 increases in obesity and metabolic syndrome.
Obese: CD8 and Th1, recruit Mac
Mac increase in obesity
Obese: more wnt5a, TNFa, SFRP5 and less adiponectin
White adipose tissue in Obese: increased macrophage infiltration
T cells: lean more Tregs
Describe a fatty artery as a “local obesity”
What will cholesterol attract?
Describe the action of macrophages.
Cholesterol in the plaque attracts M1 pro-inflammatory macrophages
Macrophages secrete the chemokine CCL2 to attract monocytes and then prohibit them from exiting
Big plaque to ruptured plaque is clinical problem of huge dimensions
What secretes CCL2 and what happens when it is secreted?
Cholesterol in the plaque attracts M1 pro-inflammatory macrophages
Macrophages secrete the chemokine CCL2 to attract monocytes and then prohibit them from exiting
Big plaque to ruptured plaque is clinical problem of huge dimensions
How are innate immune responses in the brain suppressed? (What cells and what cytokines?)
Innate immune responses in the brain are held in active suppression by microglia and Il-10 and TGF- β
Describe the 2 subsets of microglia in the CNS.
Do they act more like M1 or M2?
MHC?
What are they derived from?
2 subsets of microglia in CNS:
migrate early in development and have DC and macrophage characteristics and act like M2 Macrophages
They are highly branched and display little MHC
Other subset is perivascular and derived from circulating monocytes
What cells compose the innate immune cells of CNS?
Microglia
Astrocytes
Oligodendroytes
How will DAMPS/PAMPS be recognized in CNS? What responses will be initiated?
Activation of the glial system by DAMPS/PAMPS converts the M2 to M1 and then they secrete pro-inflammatory cytokines
They upregulate MHC and change morphology
IFNgamma, TNFalpha, IL17 to endothelial cell and astrocyte…which work as inflammation amplifiers, activation of NF-kB and IL6
Slide 37
What cytokines may be an important cause of delirium or long term traumatic brain damage?
Pro- inflammatory cytokines, especially IL-6, have potent effects on neural function and survival
May be important cause of delirium, long term traumatic brain damage
