Endocrine 8: Calcium and Phosphate; PTH

Question 1

List functions of calcium

Answer 1

• most abundant cation (because it is in bone)
• tightly regulated
• membrane stability
• neuronal transmission
• bone formation
• blood coagulation
• muscle function
• hormone secretion

Question 2

List functions of phosphates.

Answer 2

• energy metabolism
• intracellular signalling pathway
• nucleic acid backbone
• bone structure
• enzyme activation/deactivation

Question 3

What can hypocalcemia lead to?

Answer 3

• muscle failure
• tetany
• convulsions
• death

Question 4

What can hypercalcemia lead to?

Answer 4

• renal dysfunction
• calcification of soft tissue
• muscle weakness
• coma

Question 5

What can lead to hyperphosphatemia?

Answer 5

crush injury

- severe tissue injury leaks phosphate

Question 6

How is calcium transported in the blood?

Answer 6

• free
• albumin (since 50:50 ratio, measuring albumin is a good indicator of calcium)
• few complexed (phosphates, citrates)

Question 7

How is phosphate transported in the blood?

Answer 7

• mostly free

- some protein

Question 8

What are the primary regulators of calcium?

Answer 8

• PTH

- vitamin D (calcitriol)

Question 9

Define rapidly exchangeable pool.

Answer 9

• constant bone remodeling utilizes calcium storage

- main storage in bones, gut, and kidney

Question 10

List the primarily cells in the PTH.

Answer 10

• chief cells - make PTH

- oxyphil cells - increase with age and kidney decline

Question 11

Where is the parathyroid gland located?

Answer 11

on the back of the thyroid

• 4 lobes
• small

Question 12

Describe the structure of PTH.

Answer 12

• total 1-84 AA secreted
• peptide hormone (prepro => pro => hormone)
• 1-34 AA is biologically active, binds to PTH1R
• 35-84 fragment is not active, but has long half-life

Question 13

Define PTHrP.

Answer 13

PTH-related-peptide

• highly analagous to 1-34AA
• mimics PTH in bone and kidney
• many tumors produce this => hypercalcemia
• paracrine effect
• binds with equal affinity to PTH1R

Question 14

Differentiate PTH1R and PTH2R.

Answer 14

PTH1R can bind with equal affinity to PTH and PTHrP
- primary receptor
- found on osteoclasts and kidney
- GPCR
- binds 1-34, 1-84, and PTHrP
PTH2R can bind only to PTH

Question 15

What is the net effect of PTH?

Answer 15

• increase plasma Ca (via bone resorption)

- decrease plasma Pi

Question 16

Define osteoblasts.

Answer 16

• support bone mineralization and bone formation
• PTH target (high expression of PTH1R)
• derived from mesenchymal stem cells

Question 17

Define osteoclasts.

Answer 17

• bone breakdown/resorption
• derived from HSCs
• do NOT express PTH1R

Question 18

Define osteocytes.

Answer 18

• terminally differentiated osteoblasts

- found in bone matrix

Question 19

What does PTH do in the bone?

Answer 19

1. PTH binds to PTH receptors on osteoblasts
2. stimulates macrophage-colony stimulating factor (M-CSF) from osteoblasts
3. M-CSF stimulates osteoclast differentiation
4. stimulates osteoblast expression of RANK-Ligand
5. RANKL stimulates RANK expression on osteoclast
6. further osteoclast differentiation and bone resorption => release of Ca and Pi from bone into plasma
7. osteoblasts take released Ca and Pi and use it to make new bone mineralization

Question 20

Define OPG.

Answer 20

OsteoProteGerin

• soluble decoy
• antagonist to RANKL
• prevents differentiation of osteoclasts
• no bone resorption, maintains bone

Question 21

What regulates OPG?

Answer 21

• estrogen stimulates OPG => prevent bone resorption; protective in pre-menopausal women
• cortisol inhibits OPG => allow RANK activation => bone resorption

Question 22

What does PTH do in the kidney?

Answer 22

• transcription of CYP1a gene
• encodes CYP1a/1a-hydroxylase enzyme
• required for activation of Vitamin D (converts to 1,25-OH-cholecaciferol)
• allows for calcium channel insertion on apical membranes of distal tubule (increase calcium reabsorption)

Question 23

What is the primary regulator of PTH?

Answer 23

• plasma calcium levels monitored by CaSr on parathyroid gland chief cells, kidney, and thyroid calcitonin C cells
• high calcium = low PTH
• low calcium = high PTH

Question 24

Define CaSR.

Answer 24

Calcium Sensing-Receptor

• found on chief cells, kidney, C cells
• binds free Ca in the blood
• downstream signaling cascade inhibits PTH gene transcription and promotes degradation of preformed PTH

Question 25

How does Vitamin D regulate PTH?

Answer 25

- inhibits PTH gene transcription - promotes transcription of CaSR - increases PTH sensitivity to Ca (even if little Ca in the blood...will think there is enough..no PTH)

Question 26

Define calciferol.

Answer 26

any Vitamin D analog

Question 27

Define cholecalciferol.

Answer 27

Vitamin D3 from animal tissues.

Question 28

Define ergocalciferol.

Answer 28

Vitamin D2 from plant tissues

Question 29

Define calcidiol.

Answer 29

25-OH-Vitamin D (25-OH-cholecalciferol) - immediate precursor to active Vitamin D - default inactive pathway

Question 30

Define calcitriol.

Answer 30

1, 25 -OH-cholecalciferol - active form - activated by CYP1a or 1a-hydroxylase in the kidney

Question 31

How is active vitamin D synthesized?

Answer 31

1. endogenous cholesterol derivative is activated to vitamin D3 via UV light 2. transported to liver via vitamin-D binding protein or chylomicron in blood 3. liver converts it to the immediate inactive precursor (25-OH-D) 4. transported in peripheral blood attached to DBP 5. activated in the kidney via 1a-hydroxylase to 1,25-OH-D

Question 32

What regulates vitamin D activation?

Answer 32

- calcium levels (low calcium => PTH increase => bone resorption => increase plasma calcium) - phosphate levels - low Vitamin D

Question 33

What are targets of Vitamin D?

Answer 33

bone kidney gut

Question 34

Describe Vitamin D effects in bone.

Answer 34

- mobilize Ca from bone - stimulate osteoclast differentiation directly via nuclear receptors - indirect: by increasing calcium absorption and reabsorption in the kidney => increase plasma calcium => promote bone mineralization

Question 35

Describe Vitamin D effects in gut.

Answer 35

- increase transcellular calcium absorption by promoting transcription of TRPV5/6 and PMCA transport proteins

Question 36

What happens in hypocalcemic situations?

Answer 36

1. low Ca stimulates PTH release 2. PTH ===> activates CYP1a in kidney ==> Vit. D activation ==> bone resorption, dietary absorption ===> bone resorption ===> increase plasma Ca ===> reabsorption at the kidney ===> increase plasma Ca 3. negative feedback ===> vitamin D blocks PTH release ===> increased blood Ca blocks PTH and CYP1a

Question 37

Define osteoporosis

Answer 37

Causes - genetic - menopause (loss of estrogen => loss of OPG => continuous RANK stimulation => continuous resorption) - stress/glucocorticoids (cortisol increases bone resorption) - low dietary Ca Sx: reduced bone density Tx: estrogen, calcitonin, dietary Ca, bisphosphonates (inhibit bone resorption but can lead to fractures), Vitamin D

Question 38

Define hyperparathyroidism.

Answer 38

Primary Causes = hyperplasia, carcinoma at parathyroid - Sx: kidney stones, hypercalcemia Secondary Causes = chronic renal failure - reduced vitamin D production => constant PTH release

Question 39

Define pseudohyperparathyroidism.

Answer 39

- congenital defect in PTH1R G-protein - also leads to generalized resistance to PTH, LH, FSH, TSH (same G protein) - Sx: low calcium, high phosphate, high PTH, short stature

Question 40

Define hypoparathyroidism.

Answer 40

Sx: tetany, low Ca, Chvostek sign of twitching facial nerve

Question 41

Define rickets/osteomalacia.

Answer 41

rickets = bow legged, children; osteomalacia = adults - Vitamin D deficiency => unmineralized bone (soft) - decreased bone strength

Question 42

Define source and effects of calcitonin.

Answer 42

- thyroid C cells - inhibits bone resorption - hypocalcemia actions