Lecture 5 Flashcards
intestinal absorption of calcium (2 ways)
Calcitriol stimulates all of this through protein synthesis
- calcium channel (TRPV6): initial uptake of calcium across apical boarder
- passive diffusion (high Ca intake)
- two ways to cross basolateral membrane:
- good to have a backup if one doesnt work so that the immediate second option is getting it from bone
1.SODIUM CALCIUM EXCHANGER;
- 3 Na+ in and ! Ca2+ out
- build up of sodium causes problems for uptake of other nutrients like SGLT1 (needing low Na inside cell in order to transport glucose and galactose)
- CALCIUM PUMP:
- Ca2+ out and H+ in
calbindin shuttles calcium from ER stores to basolateral transporters to help maintain intestinal and blood Ca2+ levels
vital roles of calcium
- muscle contraction (skeletal, smooth)
- 2nd messenger in signalling pathways
-neurotransmitter release
have to always balance it as its vital
Parathyroid hormone
- first response in increasing blood calcium
mechanisms:
- inhibits many bone forming reactions (type 1 collagen formation, osteocalcin production) so we can send the calcium elsewhere in the blood instead
- stimulates 1-a-hydroxylase in kidney which forms calcitriol and vit D
- decreases renal Ca2+ excretion
HOW IS IT DONE SO FAST?
- pre formed PTH is stored in vesicles (cleaved until it fits into vesicles)
- pre is cleaved from pre-pro PTH and moves to ER
- pro is cleaved from pro sequence
- PTH can now be stored in vesicles and ready for release
- PTH stops when Ca binds to CaSR (calcium senseing receptor)
much faster than regular intestinal absorption of calcium where calcitriol makes proteins etc
Familial hypercalcemic hypocalciuria (FHH)
FHH mutation in the CaSR: not responsive to changes in blood Ca (body perceives a fake lack of Ca2+ and continues secreting PTH)
- will make blood Ca go outside of the homeostatic range
phenotype:
- hypercalcemia: temporarily fixed by bone resoprtion but causes risk of fractures
- hypocalciuric: low levels of Ca2+ in urine, Ca trapped in kidneys = stones
Two types of bone
Cortical Bone:
- 80 of bone mass
- outer layer of all bones and interior of long bones
- dense tissue
- provides most bone strength “therefore don’t want constant turnover”
Trabecular bone
- 20% of total bone mass
- lined by areas of osteoblasts and osteoclasts
- undergoes constant turnover
Types of mature bone cells
Responsible for continually remodelling bone
Osteoblast: bone forming cell through ossification - secrete organic matrix
- mesenchymal cell > pre osteoblast > RUNX2 (key transcription factor) > mature osteoblast
Osteoclast: bone resorting cell (breakdown), found on growth surfaces of bone (outer)
- hematopoietic cell > M-CSF (stimulates RANK expression) > pre osteoclast > RANK-L BINDS TO RANK (receptor) > mature osteoclast
Osteocyte: old osteoblasts that are embedded in bone matrix - sense mechanical stress and secrete growth factors that stimulate new osteoblasts
Bone remodelling cycle
- Osteoclast resorption:
- prepare the site for new bone formation
- osteoclast at ruffled border start to break down outer layer of bone - Osteoblast activity:
- bone matrix proteins lay down new bone (no minerals yet) - Mineralization:
- calcium and phosphorus form hydroxyapatite (bone cells)
- cross links with what’s already layed down: THIS is what makes bone resistant to compression
- need both proteins AND minerals (ex: low blood calcium = low minerals = forced to break down bone to release calcium = fractures) - Resting phase:
- process starts again to layer bone
Bone composition
Bone is composed of a tough organic matrix (70%) that is strengthened by deposits of calcium (30%)
- organic matrix also called the osteoid (70%):
- majority is type 1 collagen fibres
- ground substance made of chondroitin sulfate and hyaluronic acid (make hydroxyapatite)
- also has organized matrix of proteins produced by osteoblasts (osteoclasts and osteonectin)
Bone salts (30%):
- calcium and phosphate deposits within organic matrix
- the major crystalline salt: hydroxyapatite
Bone formation or deposition
deposition of proteins by osteoblast:
- main one being type 1 collagen (hardened by hydroxyapatite)
- other proteins lead to cross linking bone structures:
- osteocalcin: strongly binds calcium and hydroxyapatite (links bone salts to the protein)
- osteonectin: binds to hydroxyapatite AND collagen fibers, forms a lattice work holding organic matrix and bone salts together, facilitates mineralization of collagen fibers
(Continuation of bone formation and deposition):
Other proteins secreted by osteoblasts (along with type 1 collagen, osteocalcin, osteonectin) except these regulate activation of osteoclasts
RANK-Ligand (RANK-L):
- binds to RANK receptor on pre osteoclast which stimulates the cell to mature
- can be expressed on the osteoblast surface (cell contact dependent mechanism) OR
Secreted as a free protein (cell contact INdependent mechanism)
- secretion stimulated by: calcitriol, PTH, inflammatory cytokines
Osteoprotegerin (OPG)
- RANK-L antagonist: secreted and binds to RANK-L forming a complex that CANNOT bind to the RANK receptor (inhibits osteoclast maturation)
- secretion stimulated by: estrogen, IL-4
Regulation of osteoclast maturation via RANK-L and OPG
- PTH and other stimuli will stimulate osteoblast to express RANK-L
- RANK-L will bind to RANK on pre osteoclast
- RANK-RANKL signalling results in osteoclast maturation -> bone resorption
-when OPG binds to RANK-L it prevents RANKL from binding RANK receptor and prevents activation/maturation of the preosteoclast and subsequent bone resorption
the four mechanisms of osteoclast regulation
MAIN GOAL: keeping blood CA within its homeostatic range (9-10.5)
- Cell contact dependent RANK-RANKL signalling: RANKL physically comes into contact with surface of pre osteoclast and RANK receptor -> osteoclast maturation and bone resorption
- Cell contact independent RANK-RANKL signalling: pre osteoclast secretes RANKL as a free protein and comes into contact with nearby preosteoclast RANK -> osteoclast maturation and bone resorption
- Secreted OPG antagonism on osteoblast cell surface (cell contact dependent?): affects how much RANKL binds to RANK, prevents osteoclast maturation and function
- Secreted OPG antagonism within bone micro environment (cell contact independent?): prevents RANKL from binding -> prevents osteoclast maturation and function
