Physiology of Ca-Regulating Hormones

Question 1

What is the normal concentration of calcium in the serum?

Answer 1

9.5mg/dL (range: 8.5-10.5 mg/dL)

approx 50% is free (range: 4.5-5.6 mg/dL)

Question 2

Where is most of the calcium in the body housed?

Answer 2

99% of calcium is in bone

Intracellular (15)

Extracellular (0.1%)

Question 3

How does extracellular/plasma calcium exist?

Answer 3

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-)

Question 4

How much calcium should be in a daily diet?

Answer 4

1000-1200mg/day

Question 5

What is hypocalcemia defined as?

Answer 5

less than 8.5 mg/dL

hyper- 10.5+ mg/dL

Question 6

Where is most of the phosphate in the body found?

Answer 6

85% bone

14% intracellular

0.1% extracellular

Question 7

How does extracellular/plasma phosphate circulate?

Answer 7

55% free (as PO43-)

35% Cation bound

10% protein bound

Question 8

How is the majority of calcium eliminated? phosphate?

Answer 8

calcium- feces

phosphate- urine

Question 9

Normal phosphate concentration?

Answer 9

4mg/dL (range: 3-4.5 mg/dL in adults; 4.5-6.5 mg/dL in children)

Question 10

Whether calcium and phosphate are deposit in bone or ersorbed depends on what?

Answer 10

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

Question 11

Where does PTH come from?

Answer 11

chief cells of the PT gland as a 84 AA peptide

Question 12

How is PTH stimulated to be released?

Answer 12

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

Question 13

What are the main effects of PTH secretion is response to decreased ECF Ca2+?

Answer 13

• 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

Question 14

How does PTH increase Ca2+ transfer form bone fluid into the ECF?

Answer 14

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

Question 15

How does PTH promote bone resorption?

Answer 15

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

Question 16

What is the role of osteoprotegerin (OPG)?

Answer 16

This is a soluble protein secreted by osteoblasts that binds to RANKL to prevent osteoclast formation

Question 17

What things increase OPG? Decrease?

Answer 17

increase- estrogen

decrease- PTH

Question 18

Note about the use of intermittent low-dose PTH

Answer 18

This actually increases bone formation by promoting osteoblast proliferation and differentiation, while at the same time decreasing osteoblast apoptosis

Question 19

How does PTH stimulate reabsorption of Ca?

Answer 19

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

Question 20

What are the effects of PTH on proximal tubule cells?

Answer 20

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

Question 21

How is vitamin D activated?

Answer 21

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

Question 22

What stimulates 1a-hydroxylase? Inhibits?

Answer 22

stimulates; high PTH

inhibits: high calcium, vitD

Question 23

What are the main roles of 1,25(OH)2D?

Answer 23

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

Question 24

Question 25

How is GI Ca2+ absorbed?

Answer 25

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

Question 26

How does Vit D promote GI Ca and P absorption?

Answer 26

It binds to a steroid hormone receptor and stimulates expression of calbindin and epithelial Ca channels, as well as Na-PO4 channels

Question 27

How does VitD promote osteoclast-mediated bone resorption?

Answer 27

At high Conc, VitD binds to VDR on osteoblasts and increases RANKL expression and repressed OPG

Question 28

How does vitamin D inhibit PTH expression?

Answer 28

It binds to intracellular receptors in the nucleus of chief cells to inhibit synthesis

Question 29

Where is calcitonin made?

Answer 29

C cells in the thyroid gland as a 32 AA polypeptide

Question 30

What are the effects of calcitonin?

Answer 30

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

Question 31

When is calcitonin most active?

Answer 31

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

Question 32

Question 33

What is FGF23?

Answer 33

Fibroblast growth factor 23, a protein produced in bone secreted into circulation in response to increased levels of phosphate, calcitriol, and PTH.

Question 34

What does FGF23 do?

Answer 34

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

Question 35

Phosphate metabolism in healthy adults

Answer 35

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)

Question 36

Phosphate metabolism in kidney disease

Answer 36

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