Lecture 20 - Bone, Adipose tissue and CNS Flashcards
What cytokine is necessary for mesenchymal stem cell to become an adipocyte?
For osteochondral progenitor to become
- osteoblast
- chodrocyte
- adipocyte = PPAR Y
- OB –> RUNx2
- Chrondocyte –> Sox 9
OB, OC and immune cells communicate with each other through the_______ system.
MCSF: what secretes it, what is its function?
What is expressed on pre-OC and OC? What is the cytokine secreted by OB’s?
What secretes OPG and what is its function?
What determines bone formation?
- RANK-RANKL
- OB releases M-CSF that promotes OC survival and proliferation
- RANK
- RANKL is the cytokine
- OB secretes ( also stromal & immune cells), function to inhibit Rank/RANKL (modulate
- The ratio between OPG and RANKL
- Any condition that alters OR promotes OC dominance will be associated with bone pathology
What 2 cytokines are important for the differentiation and maturation of macrophage/monocyte precursors into mature OC’s?
- RANKL & M-CSF
What other cells can express RANKL? (4)
What cytokines induce RANKL and promote OC?
What inhibits OC?
Both innate & adaptive immune cells
- Monocytes
- Neutrophils
- DC
- T & B cells
Pro inflammatory cytokines:
1,6,8,
TNF
and especially 17 !!!!
ANTI - Inflammatory inhibit:
a) IL - 4 and IL - 10
b) ESTROGEN (sex hormones)
A dominant _____ response in and around bone is associated with INF- and activated macrophages.
Result?
What other cells are potent OC activators?
What inhibits Il-17? Good or bad?
- Th1
- pro-clastogenic and bone resorption
(RANK/RANKL overload) - Th17
(rheumatoid arthritis*) - A normal Th1 or TH2 response or balanced TH1/Th2 responses would strongly inhibit IL 17. result: a good thing!!
What is rheumatoid arthritis?
What infiltrates?
What drives this? (cytokine)
Which cytokine specifically makes more RANKL and promotes OC differentation/proliferation?
- Destroys joints by eroding bone
- Infiltration with Th17!!!!
- Inappropriate synovial based DC release of
IL - 23 , IL -17 and uncontrolled OC activity
** IL-17 stimulates OB to make more RANKL and promotes OC differentiation and proliferation
[The RANK/RANKL/OPG balance is pro-bone loss and causes bony erosions and loss of joint function]
What cells are found in the synovium of joints of Rheumatoid Arthritis patients?
What is an effective treatment for osteoporosis
if B or T cells are the source of excess RANKL, what can block this?
Th17!!!
MONOCLONAL antibodies
- treatment with Denosumab
Premenopausal state: _____ promotes normal OB & OC function
Post menopausal state: _____ balance is altered
High levels of _____cause net increase in OC activity
- estrogen
- promotes Th17 proliferation and production of IL-17 - OPG/RANKL
- RANKL
- Blocking RANKL with a monoclonal antibody can lead to decreased bone loss
What is the largest endocrine organ that produces a wide array of hormones that act like cytokines and vice-versa.
Adipose tissue!!!!
-Any stimulus that increases inflammation in adipose tissue is a VERY bad thing
The following describe what?:
- 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
WHITE ADIPOSE TISSUE (WAT)
What are the 2 major types of macrophages?
Which is pro and which is ANTI inflammatory?
What are the macrophage cytokines in WAT that are pro-inflammatory?
- M1 = PRO- inflammatory
- M2 = ANTI- Inflammatory
- Osteopontin and Resisting
Osteopontin - pro-inflammatory and potent chemotactic signal for monocytes and macrophages
Resistin - antagonist of adiponectin
Uses: Il- 1, 6 , 8 and
TNF-a
What is the function of the following ADIPOCYTOKINES: (which is pro & which is anti-inflammatory?)
- Leptin
(cytokines? - Adiponectin
- MAC - 1 (macrophage inhibitory cytokine)
- Visfatin
Leptin: pro-inflammatory, decreases appetite, increase IL-1, 6, and TNF - gamma by macrophages (& other cells)
- Adiponectin - ANTI - inflammatory, predominantly by suppression of TNF - a
* * antagonist to leptin** - MAC - 1: TNF superfamily - promotes ADIPONECTIN release
- anorexigenic
- serum levels have negative correlation with body fat - Visfatin: suppressed in WAT and is PRO- INFLAMMATORY and PRO- ANGIOGENIC
State which of the following this describes:
- suppressed in WAT and is PRO- INFLAMMATORY and PRO- ANGIOGENIC
- ANTI - inflammatory, predominantly by suppression of TNF - a
* * antagonist to leptin** - Pro-inflammatory, decreases appetite, increase IL-1, 6, and TNF - gamma by macrophages (& other cells)
- TNF superfamily - promotes ADIPONECTIN release
- anorexigenic
- serum levels have negative correlation with body fat
- Visfatin
- Adiponectin
- Leptin
- MAC - 1:
What is the normal WAT in non-obese humans? Net effect?
What is the macrophage population? (M1 or M2)
Cytokines? (2)
Yin/yang relationship between inflammatory (leptin/visfatin) and anti-inflammatory adipocytokines (adiponectin, SFRP, and MAC-1)
net effect: of slightly anti-inflammatory milieu in health
- M2!!!
- upregulate production of IL-4 and IL-10, attenuate NFkB, promote repair of tissue
In OBESE WAT:
- What is not present?
- What does expanding fat trigger (“stuffing” of adipocytes with fat)?
- What carries the problem into the liver and into plaques?
- What do “stuffed” adipocytes release? (specifically 1)
What may have strong influence on the development of OBESITY?
- Yin/yang relationship between inflammatory and anti-inflammatory adipocytokines is not present
- Expanding fat in adipocytes triggers a very dangerous signaling program that makes WAT very PRO-INFLAMMATORY by recruiting large # of monocytes and macrophages into it*** (key)
- eventuates in INSULIN RESISTANCE - PORTAL VEIN
- Release pro-inflammatory cytokines and CHEMOTACTIC cytokines
= CCL2
(monocyte chemoattractant protein1) - GUT MICROBIOTA
