hormonal regulation of calcium and phosphate balance Flashcards
what are the 3 hormones that regulate ca2+ and phosphate levels?
Parathyroid hormone (PTH)
1,25-dihydroxyvitamin D
Calcitonin
what type of hormone is parathyroid hormone (PTH)
Peptide hormone
when and where is PTH secreted?
Secreted by the chief cells of the parathyroid gland in response to low plasma Ca2+ levels
how is PTH levels regulated by plasma calcium levels?
calcium binds to CasR in the parathyroid. This causes arachidonic acid to be synthesized in the cell. AA inhibits the synthesis of PTH.
When calcium levels are low, this pathway isn’t inhibited so PTH can be released from the parathyroid.
where are the 2 main targets of PTH?
bone and kidney cells
where is the large majority of calcium and phosphate stored?
bones
what is the structure of the bone?
a connective tissue containing several cell types surrounded by a protein matrix (called osteoid), mainly containing collagen.
The organic matrix is mineralised by hydroxyapatite, a calcium-phosphate-hydroxide salt.
Bone is a highly dynamic structure.
what do osteoblasts do?
mediate bone formation:
They secrete collagen and other proteins such as osteocalcin and osteopontin (collectively called “osteoid”)
Ca2+ and PO43- become associated with this new bone matrix. This process is called mineralisation
Osteoblasts can become osteocytes upon being embedded in the bone matrix. They can also be removed by apoptosis or become inactive bone-lining cells
what do osteoclasts do?
mediate bone reabsorption:
Osteoclasts attach tightly to the surface of bone
They secrete proteases and H+ ions
H+ ions dissolve the hydroxyapatite crystals and expose the organic matrix, allowing degradation of collagen by proteases (e.g. collagenases)
This results in release of Ca2+ and PO43- from bone
what does PTH do?
stimulates calcium resorption from the bone by acting on PTH receptors on osteoblasts and increasing RANKL and decreasing osteoprotegerin which allows RANK to bind to RANKL and this cause osteoclast precursor cells to differentiate into osteoclast cells which stimulate calcium and phosphate resorption from the bon
why doesn’t PTH act directly on osteoclasts?
osteoclasts lack a PTH receptor protein.
how does PTH stimulate bone reabsorption?
PTH (a peptide hormone) binds to PTH receptors on osteoblasts. This leads to an increase RANK and a decrease in osteoprotegerin which allows RANK to bind to RANKL and cause differentiation of osteoclast precursours into osteoclasts.
osteoclasts then cause resorption by releasing hydrogen ions which dissolve the hydroxyapitite crystals and expose the matrix. Proteases then break down the matrix resulting in the release of calcium and phosphate into the blood.
how does inhibiting osteoprotegerin stimulate the production of osteoclasts (osteoclastogenesis)
osteoprotegerin blocks RANK from binding to RANKL. By inhibiting production of osteoprotegerin it allows RANKL to bind to RANK.
what effect does PTH have on the reabsorption of calcium and phosphate in the kidneys?
- Ca2+ reabsorption increases due to PTH stimulation of Ca2+ transporter expression and activity
- PO43- reabsorption decreases due to PTH-stimulated internalisation and lysosomal degradation of a PO43- transporter (i.e. removal from the plasma membrane)
- The enhanced excretion of PO43- is important to prevent plasma levels of this ion rising as a result of increased resorption from bone and increased absorption from intestine
paratyhyroid hormone also causes synthesis of 1,25-dihydroxyvitaminD, what is1,25-dihydroxyvitaminD?
Vitamin D can be synthesised in the body (requires sun exposure; UV light) or obtained from ingested food
1,25-dihydroxyvitamin D is the biologically active form of Vitamin D (also called calcitriol)
how does PTH increase 1,25-dihydroxyvitamin D synthesis?
PTH achieves this effect by up-regulating expression of 25-Hydroxyvitamin D 1-alpha-hydroxylase in kidney
this is the enzyme which converts 25- hydroxyvitaminD to 1,25-dihydroxyvitaminD
what type of hormones is 1,25-dihydroxyvitamin D ?
steroid hormone
what does 1,25-dihydroxyvitamin D do?
regulates calcium and phosphate levels
Main effect of 1,25-dihydroxyvitamin D is on intestines
Increases Ca2+ absorption
Increases PO43- absorption
These effects are by increased expression of Ca2+ and PO43- transporter proteins
1,25-dihydroxyvitamin D also has effects on kidneys
Increases Ca2+ reabsorption by increasing expression of transporter protein
1,25–dihydroxyvitamin D protects bone from the actions of PTH by increasing Ca2+ uptake from GI tract…and therefore reducing PTH secretion
what is The mechanism involved in 1,25-dihydroxyvitamin D regulation of Ca2+ absorption
1)Enter cells
2)Activates receptor in the nucleus
3)Increased transcription/expression of Ca2+ transporter proteins
4)Leads to increased absorption of Ca2+
By a similar mechanism increases expression of Ca2+ transporters in kidneys to enhance reabsorption
how much vitamin D do babys up to 1 year of age need?
- Babies up to 1 year of age need 8.5 to 10 micrograms a day
how much vitamin D do children and adults over 1 year need?
- Children from age of 1 year and adults needs 10 micrograms a day- includes pregnant and breastfeeding women
what does calcitonin do?
lowers blood calcium and phosphate levels:
Inhibits both the activity and differentiation of osteoclasts.
thus inhibits resorption and promotes deposition
However, most evidence suggests that calcitonin plays little role in the normal regulation of Ca2+ and PO43- balance in humans
May play a role in protecting skeletal integrity when there is a high Ca2+ demand such as during pregnancy or breast-feeding
where is calcitonin secreted?
Secreted by the C-cells (aka parafollicular cells) of the thyroid gland in response to an elevation in plasma Ca2+ levels
CT receptor is a GPCR. Two main sites of action are osteoclasts in bone and kidney cells
