Calcium and Phosphate

Question 1

In which body tissue is >99% of the body’s calcium stored?

Answer 1

Bone

Question 2

Is intracellular calcium concentration very low?

Answer 2

Yeah

Question 3

True or false: roughly half of all plasma calcium is bound to proteins, and half is diffusable (ionized or complexed to HCO3-, etc.).

Answer 3

True

Question 4

What are the effects of vitamin D and PTH on phosphate homeostasis?

Answer 4

Vitamin D promotes phosphate absorption in the GI tract.

PTH promotes phosphate reabsorption from bones but inhibits phosphate reabsorption in the kidneys - net effect is LOSS OF PHOSPHATE.

Question 5

True or false: concentrations of calcium phosphate in the blood are near the solubility product in order to successfully deposit bone, so a slight elevation in levels can cause precipitations, stones, etc.

Answer 5

Tru dat

Question 6

Name three things that osteoblasts use during bone formation and what the purpose of each is.

Answer 6

1. Type 1 collagen: provides scaffolding for the nucleation of bone minerals.
2. Osteocalcin: binds calcium and hydroxylapatite.
3. Osteonectin: binds hydroxylapatite and collagen fibers.

Question 7

Calcium in bones turns over at a rate of ____% per year in infants and ____% per year in adults.

Answer 7

100% in infants, 18% in adults

Question 8

How long does a local cycle of bone resorption and replacement take?

Answer 8

100 days

Question 9

What is the general effect of PTH and D3?

Answer 9

To increase blood Ca2+

Question 10

What is the general effect of calcitonin?

Answer 10

To decrease blood Ca2+

Question 11

What are the two major tissues that respond to PTH? What happens in them?

Answer 11

In bone: increases resorption.
In kidneys: increases reaborption of calcium and increases conversion of 25-hydroxycholecalciferol to 1, 25-dihydroxycholecalciferol (active D3).

Question 12

True or false: PTH is produced by chief cells and stored as secretory granules in vesicles until secreted.

Answer 12

True

Question 13

How do calcium levels regulate PTH secretion by chief cells?

Answer 13

When Ca2+ levels are high, they bind heterotrimeric G protein receptors (calcium-sensing receptor, CaSR) on chief cells, causing INHIBITION of PTH release. When Ca2+ levels drop, calcium dissociates from the receptor –> release of PTH via vesicle fusion.

Question 14

Can PTH secretion be completely shut off even at very high calcium levels?

Answer 14

Nope

Question 15

PTH is synthesized as ________ that is cleaved twice more to produce the active hormone.

Answer 15

pre-propeptide (preproPTH)

Question 16

______ cells in the liver degrade PTH, and its half-life is ____ minutes.

Answer 16

Kupffer cells degrade it, half life is 10 minutes

Question 17

Describe the PTH receptor and how it works.

Answer 17

PTH binds to PTH 1R receptors –> activation of two G proteins:

• G alpha q activates PLC –> DAG, IP3 –> activation of Ca-dependent kinases.
• G alpha s activates adenylyl cyclase –> cAMP.

Question 18

What effects does PTH have on phosphate homeostasis in the kidneys?

Answer 18

It reduces reabsorption of phosphate in the PCT and DCT because it promotes endocytosis of Na+/Pi cotransporters from the apical cell membranes –> phosphaturia and lower plasma phosphate.

Question 19

Describe the mechanism by which PTH increases osteoclast differentiation and bone resorption.

Answer 19

PTH binds to receptors on osteoBLASTS –> expression of M-CSF, RANKL, and IL-6 –> increased macrophage to osteoclast differentiation.

Question 20

What is the function of OPG?

Answer 20

It inhibits osteoclast differentiation by binding to RANKL, preventing its interaction with RANK on osteoclast progenitor cells.

Question 21

Pulsatile, low-dose secretion of PTH can actually result in bone _______ by stimulating osteocytes to transfer Ca2+ to osteoblasts.

Answer 21

results in bone formation (how paradoxical!)

Question 22

What is PTH-related protein (PTHrp) and what does it do?

Answer 22

Both PTH and PTHrp bind to PTH 1R but PTHrp is associated with cartilage growth and development in utero and with Ca++ transport in the placenta.

Question 23

Describe the synthetic pathway of active D3. Which reaction is under the control of PTH?

Answer 23

7-dehydrocholesterol –> cholecalciferol in skin from sun exposure –> 25-hydroxycholecalciferol in liver –> 1,25-dihydroxycholecalciferol in kidneys (active form) using the enzyme 1a-hydroxylase.

PTH promotes the final hydroxylation at the C1 position.

Question 24

Where do peeps get vitamin D2? How does it differ from D3? Is it as active as D3?

Answer 24

From diet - veggies, fish, tofu. D2 has an extra 2x bond between carbons 22 and 23. Not as active as D3.

Question 25

Where in the body is vitamin D stored? How does it get around in the plasma? What percentage of it is turned over per day?

Answer 25

Stored in adipose (its a fat-soluble vitamin). Gets around in the plasma on proteins or in chylomicrons. 1-2% is turned over per day.

Question 26

What is the cellular location of the vitamin D receptor?

Answer 26

Nucleus - its a steroid hormone

Question 27

By what mechanisms does vitamin D act on enterocytes to increase calcium absorption from the GI tract?

Answer 27

Vitamin D increases synthesis of apical Ca2+ pumps, channels, and calbindin (a protein that binds Ca2+ inside cells to maintain a gradient for further absorption)

Question 28

What effect does Vitamin D have on phosphate homeostasis in the GI tract? How?

Answer 28

It increases phosphate absorption by increasing synthesis of the 2Na+/Pi apical co-transporter in the small intestine

Question 29

What is the effect of vitamin D on the kidneys?

Answer 29

It acts with PTH to increase calcium reabsorption in the DCT. It also increases phosphate reabsorption but the effects of PTH (inhibition of phosphate reabsorption) outweigh the effects of vitamin D.

Question 30

Does vitamin D inhibit the final hydroxylation of 25-hydroxycholecalciferol?

Answer 30

Yeah

Question 31

Describe the direct and indirect effects of vitamin D on bone.

Answer 31

Direct effects: Vit D binds to osteoblasts --> secretion of matrix dissolving enzymes. It also promotes osteoclast differentiation. Indirect effects: once blood calcium is increased, bone mineralization is resumed.

Question 32

How do you keep bone loss from occurring in mice that have no vitamin D receptors?

Answer 32

Give them calcium and phosphate supplements.

Question 33

In what organ is calcitonin made and stored? What stimulates its secretion?

Answer 33

Inferfollicular cells in the thyroid make and store it. High plasma Ca2+ levels stimulate its secretion.

Question 34

Which tissues and cells are the targets of calcitonin?

Answer 34

1. Osteoclasts - calcitonin binds to G-protein receptors --> adenylyl cyclase or PLC --> inhibition of resorptive activity. 2. PCT cells in kidney --> inhibition of phosphate transport and produces mild calciuresis.

Question 35

What clinical disorders does vitamin D deficiency cause in children and adults, respectively?

Answer 35

Rickets in children, osteomalacia in adults.

Question 36

What is FGF-23 and what does it do?

Answer 36

Made in bone, stimulated by increased phosphate in serum. Binds Klotho FGF receptor --> increased phosphate secretion in kidneys, suppresses final hydroxylation of D3, and suppresses PTH production.

Question 37

Mutations in of FGF-23 cause autosomal dominant ________ _________.

Answer 37

causes autosomal dominant hypophosphatemic rickets

Question 38

The most important target tissues of PTH are: a) intestine and bone b) kidney and bone c) intestine and kidney d) parathyroids and bone e) bone and skin

Answer 38

b) kidney and bone

Question 39

The conversion of 25-hydroxycholecalciferol to 1,25-dihydroxycholecalciferol occurs in the ________ and requires the hormone ______. a) liver, UV light b) liver, PTH c) kidney, CT d) kidney, PTH e) skin, UV light

Answer 39

d) kidney, PTH

Question 40

A 50 year old man presents with low serum calcium and high serum phosphate. What is the most likely cause of these symptoms? a) hypoparathyroidism b) hyperparathyroidism c) vitamin D deficiency d) Cushing's syndrome

Answer 40

a) hypoparathyroidism

Question 41

What is calcitriol?

Answer 41

Same thing as active D3