Bone Physiology - Endocrine Flashcards
What are the six important roles the skeleton plays?
support
protection
movement
blood cell production
mineral stores
endocrine control
What characteristic of cancellous bone gives rise to its strength?
the cross struts that are intrinsically part of its structure
What bone do the neural crest cells give rise to? The sclerotome? The lateral plate mesoderm?
neural crest - craniofacial bone
sclerotone - most axial skeletons
lateral plate mesoderm - limb mesenchyme
What are the properties of the mineral phase of bone?
nano-crystalline and highly substituted analog of the naturally occurring mineral hydroxylapatite
major substituents are carbonate, magnesium, and acid phosphate, along with other trace elements the content of which depends on diet and environment
What are the cellular constituents of the skeleton?
chondrocytes
osteoblasts
osteocytes
Describe the differentiation and formation of osteoclasts.
a member of the monocytehacrophage family and a polykaryon that can be generated in vitro from mononuclear phagocyte precursors
principal physiological osteoclast precursor is the bone marrow macrophage
hematopoietic stem cell commits after expression of PU.1
after a series of differentiation, they fuse and form giant cells
they then attach to bone and lead to bone resorption
can also release bone-derived factors to communicate with other cells, the osteoblasts
What is the action of osteoclasts?
resorbs bone by secreting acid to degrade the structure
acid hydrolases and other ensymes allow for the generation and secretion of acid
generates hydrogen ions through carbonic anhydrase 2
What is the cross-talk between principal bone cells?
resorption of specific bone matrix releases factors that regulate the cells
direct cell to cell contact: OB derived: Osteoprotegerin-RANKL and ephrine
synthetic products from each cell influence the other cell - paracrine signaling
What are the two cytokines essential and sufficient for basa osteoclastogenesis?
RANKL and macrophage colony stimulating factor (M-CSF or CSF-1)
What is RANKL and what is its role?
paracrine molecule that allows osteoblast control of osteoclastic acivity
soluble RANKL goes to a mature osteoclast, which expresses the receptor called RANK
when RANKL binds to RANK, the osteoclast resorbs bone
osteocytes in bone can also secrete RNAKL and influence the osteocyte
circulating soluble RANKL can also go to a precursor osteoclast and cause it to differentiate and mature
What is the function of M-CSF?
contributes to the proliferation, survival, and differentiation of osteoclast precursors
also important for the survival and cytoskeletal rearrangement required for efficient bone resorption
What is the role of OPG?
osteoprotegerin - decoy receptor
if RANKL binds to OPG, then it blocks the function of the molecule
this shuts off the cell - an osteoclast bound with OPG is not active and won’t have more precursor cells
osteoblast can present RANKL or OPG directly to precursor cells
can also bind directly to RANKL
What is the signaling pathway of the RANK receptor?
activates TRAF-6 and a signaling cascade results in differentiation or anti-apoptosis and cytoskeletal reorganization (through Akt)
What happens when OPG is upregulated?
the differentiation of new osteoclasts is limited, and bone becomes much more dense because no bone is being resorbed
What happens when OPG is knocked out?
there is too much differentiation and bone resorption, which results in brittle bones and lack of structure
What happens when RANKL is knocked out?
the phenotype is the same as the OPG upregulation
lack of differentiation and bone resorption
What happens when RANK is knocked out?
same phenotype as RANKL knockout and OPG upregulation
lack of signaling will lead to higher bone density and lack of osteoclast differentiation
What are the cytokines involved in osteoblast differentiation?
Hedgehogs
bone morphogenetic proteins (BMPs)
TGF-P
PTH
WNTs
stages of osteoblast differentiation
proliferation
extracellular matrix deposition
matrix maturation
mineralization
What are the roles of osteocytes?
cell body with long dendritic processes that end on right on the capillary in the bone as though these tentacles are neuro-sensing
mechanosensor
transducer
biosynthetic factor
How is the osteocyte activated?
mechanosensor
shear stress leads to opening of channels and activation of receptors that lead to more osteoblast formation
osteoclasts are downregulated in these cases
Wnt signaling pathway is important
increased OPG, decreased RANKL promoting bone formation
What is the role of sclerostin and what is its signaling pathway?
sclerostins are products of the signaling pathways that shuts off osteoblasts
when it is not active, there is osteoblast activity
presence of sclerostin is a way to inactivate the osteoblast
signaling through activation of a membrane receptor that leads to activation of the APC complex
Describe the progression of bone growth as we age.
initial increase in bone mass, peak is round 20 years of age
preserved for abut 30-40 years until it begins to decrease
after a certain point, there is a increasing risk of a spontaneous fracture
bone also grows linearly, which makes the teenage years a risk for fracture as well because the middle of the bone is yet to be filled in
What happens during bone modeling?
bone is hollowed out, marrow cavity grows larger, bone lengthens
osteoblastic bone progression, endocortical surface made larger by osteoclasts
osteoblasts are on the outer surface
