What is the normal concentration of calcium in the serum?
9.5mg/dL (range: 8.5-10.5 mg/dL)
approx 50% is free (range: 4.5-5.6 mg/dL)
Where is most of the calcium in the body housed?
99% of calcium is in bone
How does extracellular/plasma calcium exist?
45-50% free (hormone regulated)
40% protein bound (albumin). NOTE: an increase in pH (basic) leads to increased affinity of albumin (makes it more negatively charged) to calcium causing hypocalcemia (cramps, pain, paresthesias, and spasms)
10-15% anion-bound (HCO3-, PO4-)
How much calcium should be in a daily diet?
What is hypocalcemia defined as?
less than 8.5 mg/dL
hyper- 10.5+ mg/dL
Where is most of the phosphate in the body found?
How does extracellular/plasma phosphate circulate?
55% free (as PO43-)
35% Cation bound
10% protein bound
How is the majority of calcium eliminated? phosphate?
Normal phosphate concentration?
4mg/dL (range: 3-4.5 mg/dL in adults; 4.5-6.5 mg/dL in children)
Whether calcium and phosphate are deposit in bone or ersorbed depends on what?
the PRODUCT of their concentrations rather than on their individual concentrations. Thus, increased ECF concentration of either Ca2+ and PO43- favors bone mineralization (i.e. an increase in ECF PO43- alone would promote bone formation and decrease Ca2+ in serum)
NOTE: High plasma Ca-P product also favors deposit in soft tissues, increasing the risk of CV calcification
Where does PTH come from?
chief cells of the PT gland as a 84 AA peptide
How is PTH stimulated to be released?
Typically, high levels of ECF Ca2+ are sensed by a GCPR called calcium-sensing receptor, CaSR, on the parathyroid chief cells, which inhibits PTH release via a PKC mediated rise in intracellular Ca2+ which inhibits vesicle exocytotsis of PTH. When Ca2+ levels, fall, this inhibition is lost
-high levels of PO4, marginal decreases in serum Mg2+ (NOTE: large decreases in Mg2+ DECREASE PTH release), decreases in vitD
Most common causes of Mg2+ loss: diarrhea, aminoglgycosides, diuretics, alcohol abuse
What are the main effects of PTH secretion is response to decreased ECF Ca2+?
-increased Ca2+ reabsorption and decreased phosphate reabsorption by the renal tubules (aka phosphate trashing hormone)
-increased bone resorption, increasing Ca2+
-activation of vitD, which increased intestinal Ca2+ absorption
-increased urine cAMP
How does PTH increase Ca2+ transfer form bone fluid into the ECF?
Bone is immersed in an aqeuous solution containing Ca2+ and PO4 and this Ca is seperated from the ECF by an osteocytic membrane formed by osteocytes and osteoblasts (and lining cells) but is readily exchanged with the ECF. PTH increased the permeability and pump action of this osteocytic membrane, while simultaneously lowering the Ca-P product to promote demineralization
How does PTH promote bone resorption?
PTH binds to PTHR1 receptors on osteoblast membranes and stimulates the expression of RANKL. RANKL on the osteoblasts then binds to RANK on osteoclast precursors to activate gene transcription to differentiate into mature osteoclasts
What is the role of osteoprotegerin (OPG)?
This is a soluble protein secreted by osteoblasts that binds to RANKL to prevent osteoclast formation
What things increase OPG? Decrease?
Note about the use of intermittent low-dose PTH
This actually increases bone formation by promoting osteoblast proliferation and differentiation, while at the same time decreasing osteoblast apoptosis
How does PTH stimulate reabsorption of Ca?
PTH binds to principal cells in the distal nephron via a Gs associated receptor which activates PKA which:
stimulates insertion of epithelial calcium channels in the luminal membrane and extrusion pumps of the basolateral membrane
What are the effects of PTH on proximal tubule cells?
Binding of PTH to Gs associated receptors causes PKA to phosphorylate NERF (sodium hydrogen exchange regulatory factor) which causes sodium-phosphate cotransporters to be released from the luminal membrane to clathrin coated pits where they are degraded by lysosomes.
PTH also stimulates the expression and activation of 1a-hydroxylase here which activated VitD3
How is vitamin D activated?
Provitamin D (7-dehydrocholesterol) in the skin is converted to cholecalciferol by UV light which is then transported to the liver where it is hydroxylated to 25(OH)D, the major circulating form of vitamin D.
25(OH)D then circulates the kidney and is converted to 1,25(OH)2D via 1a hydroxylase in the proximal tubules OR to the less active 24,25(OH)2D
What stimulates 1a-hydroxylase? Inhibits?
stimulates; high PTH
inhibits: high calcium, vitD
What are the main roles of 1,25(OH)2D?
increases calcium and phosphate absorption from the intestine (major effect)
increases renal calcium and phosphate reabsorption
increases bone mineralization and resorption at high doses
decreases PTH formation by the parathyroids as a feedback
How is GI Ca2+ absorbed?
Transcellular Ca transport from the GI to the ECF requires 3 steps:
1) passive entry into epithelial Ca channels through ECaC channels
2) bindings to calbindin to help diffuse to the basolateral membrane
3) extrusion into ECF via Ca-ATPase and Na-Ca exchangers
How does Vit D promote GI Ca and P absorption?
It binds to a steroid hormone receptor and stimulates expression of calbindin and epithelial Ca channels, as well as Na-PO4 channels
How does VitD promote osteoclast-mediated bone resorption?
At high Conc, VitD binds to VDR on osteoblasts and increases RANKL expression and repressed OPG
How does vitamin D inhibit PTH expression?
It binds to intracellular receptors in the nucleus of chief cells to inhibit synthesis
Where is calcitonin made?
C cells in the thyroid gland as a 32 AA polypeptide
What are the effects of calcitonin?
lowers plasma Ca2+ and phopshate conc by:
-reducing bone resorption by inhibiting osteoclasts
-inhibiting renal tubular cells reabsorption of Ca2+ and phosphate
-delays calcium GI absorption
When is calcitonin most active?
Calcitonin protects against calcium loss from the skeleton during periods of heavy calcium mobilization, such as during pregnancy and especially lactation. It is also active in children but is NOT a major regulator of Ca2+ in adults
What is FGF23?
Fibroblast growth factor 23, a protein produced in bone secreted into circulation in response to increased levels of phosphate, calcitriol, and PTH.
What does FGF23 do?
acts in the kidneys to decrease expression of Na-P cotransporters and decrease production of calcitriol by inhibiting 1a-hydroxylase, resulting in hypophosphatemia.
FGF23 also reduces PTH expression
Phosphate metabolism in healthy adults
In healthy adults, phosphate intake is matched by phosphate excretion in feces and urine, and the flux of phosphate between the skeleton and the extracellular phosphate pool is approximately the same. 70% of phosphorus intake is excreted in urine (only 10% of calcium is)
Phosphate metabolism in kidney disease
In patients with kidney failure, you see decrease in renal phosphate excretion, resulting in hyperphosphatemia leading to increased risk of vascular calcification and high PTH