Bone and Fat Flashcards
Where do osteoclasts and osteoblasts originate from?
- HSCs => preosteoClasts => osteoClasts
- mesenchymal stem cells => preosteoBlasts => osteoBlasts => osteocytes
What else originates from mesenchymal stem cells?
- adipose
- chondrocytes (cartilage)
Describe the effects of Wnt on osteoclast/osteoblast differentiation.
- promotes differentiation of mesenchymals => preosteoblast
- inhibits other differentiation pathways (i.e. chondrocytes) - promotes differentiation of mesenchymals => mature osteoblasts
- inhibited BY TNFa => DKK1
How do osteoblasts affect osteoclast differentiation?
- expression of RANKL => bind to RANK on premature osteoclasts => mature osteoclasts
- mature osteoblasts secrete OPG => sequesters RANKL => inhibits differentiation of osteoclasts
- M-CSF promotes OC survival
What are RANK/RANKL?
- part of TNFa superfamily
- regulates formation of multinucleated osteoclasts
- maintains osteoclasts population for bone remodeling
- RANK is expressed on pre-OC and OC
- RANKL is secreted by OB
Define OPG.
OsteoProteGerin
- binds to RANKL
- inhibits osteoclast differentiation
- protective in premenopausal women
- made by OB
What is an important determinant of bone mass and skeletal integrity?
RANKL/OPG balance
Define M-CSF.
Macrophage Colony Stimulating Factor
- released by OB
- promotes OC survival and maturation
Describe the effects of PTH on bone resorption.
- low calcium levels stimulate PTH release from parathyroid
- PTH binds to osteoblasts
- osteoblasts secrete RANKL and M-CSF
- promotes osteoclast maturation
Which immune cells express RANKL?
- neutrophils
- monocytes
- DC
- T and B lymphocytes
What is the effect of proinflammatory cytokines on bone?
IL-1, IL-6, IL-8, TNFa, IL-17
- induce RANKL
- promote OC maturation
==> bone resorption
What is the effect of anti-inflammatory cytokines on bone?
IL-4, IL-10
- inhibit OC maturation
==> protect bone
What is the effect of sex hormones on bone?
estrogen stimulates OPG
- OPG inhibits RANKL and OC maturation
- prevent over-resorptions
- protects and maintains bone integrity
Why is maintaining a Th1/Th2 response balance important for bone integrity?
- Th1 inflammatory response via IFNg and macrophages causes OC maturation and bone resorption
- Th17 is also a potent OC activator
- having a balanced Th1/Th2 response will inhibit Th17 => prevent too much bone resorption
Describe the mechanism of Rheumatoid Arthritis.
- high levels of IL-23 in the synovium
- recruits Th17 cells to the joint
- IL-17 activates OC maturation
- RANK/RANKL/OPG balance favors bone loss => bone erosion => loss of joint function
Describe the mechanism of Osteoporosis.
- low levels of estrogen => low OPG => high levels of RANKL => promotes OC maturation
What is a potential treatment for bone cell imbalance related disorders?
Denosumab
- inhibits RANKL
- restores balance
Define White Adipose Tissue (WAT).
- endocrine organ critical for homeostasis
- produces hormones, chemokines, cytokines
- regulates energy storage/expenditure, body mass, immune response
- composition: pre-adipocytes, adipocytes, stromal cells, macrophages
Describe the types of macrophages.
M1 = pro-inflammatory M2 = anti-inflammatory
Define osteopontin.
- made by macrophages in adipose
- pro-inflammatory
- recruits monocytes and macrophages to adipose tissue
Define resistin.
- made by macrophages in adipose
- inhibits adiponectin (makes insulin)
- promotes insulin resistance
Define leptin.
- adipocytokine
- controls satiety
- pro-inflammatory
Define adiponectin.
- adipocytokine
- makes insulin
- anti-inflammatory
Define macrophage inhibitory factor.
- adipocytokine
- behaves like TNFa
- promotes adiponectin
