Calcium and Phosphate Regulation

Question 1

What is the normal range of Ca?

Answer 1

Tightly regulated range in plasma (2.2 - 2.6 mM)

Question 2

What is the most abundant cation?

Answer 2

Calcium

Question 3

What is the function of phosphate?

Answer 3

Cellular energy metabolism (ATP)
Intracellular signaling pathways 
Nucleic acid backbone
Bone structure
Enzyme activation/deactivation

Question 4

What is the function of calcium?

Answer 4

Membrane stability and cell function
Neuronal transmission
Bone structure/formation 
Blood coagulation
Muscle function Hormone secretion

Question 5

What is Ca found as in the plasma?

Answer 5

Half Ca is bound to albumin

Half is ionized

Question 6

What is Pi found as in the plasma?

Answer 6

Most of Pi is ionized

Question 7

What does hypocalcemia result in?

Answer 7

Muscle failure, tetany, convulsions, death

Question 8

What does hypercalcemia result in?

Answer 8

Renal dysfunction, calcification of soft tissues, muscle weakness, coma

Question 9

What often causes hyperphosphatemia?

Answer 9

Result of severe tissue injury “crush”

Question 10

What are the main 2 regulators of calcium?

Answer 10

PTH

Vitamin D

Question 11

What is the function of the chief/principal cells in the parathyroid gland?

Answer 11

Make PTH

Question 12

What is the function of the oxyphil cells in the parathyroid gland?

Answer 12

No known function, increase with age and chronic kidney disease

Question 13

What is the function of the 1-34 PTH fragment (N terminal)?

Answer 13

N-terminal fragment 1-34 biologically active – binds to PTH receptor

Question 14

What is the function of the 35-84 PTH fragment?

Answer 14

C-terminal fragment 35-84 has longer half-life than other fragments – inactive

Question 15

What is the clinical importance of the 1-84 PTH fragment?

Answer 15

Intact 1-84 fragment: half-life of 4 min and is clinically measured.

Question 16

How is PTH synthesized?

Answer 16

The signal peptide directs it to the ER for processing after translation

Question 17

What is the function of PTHrP (related peptide)?

Answer 17

Parathyroid hormone-related peptide (PTHrP) is highly homologous to PTH 1-34 AA.

It mimics the action of PTH in the bone and kidney.

Question 18

What is the relationship of PTHrP to disease?

Answer 18

Many tumors produce PTHrP (renal, bladder, lymphoma, head/neck) resulting in hypercalcemia

Question 19

What are the PTH receptors?

Answer 19

PTH 1R

PTH 2R

Question 20

Describe PTH 1R.

Answer 20

Primary receptor and is found in the osteoblasts and kidney and it is a GPCR.

Binds 1-34 fragment, 1-84, PTHrP

Question 21

Describe PTH 2R.

Answer 21

Physiological importance in humans unclear

Binds 1-34
Does not bind PTHrP

Question 22

What are the targets of PTH?

Answer 22

Bone and Kidney

Question 23

What are the effects of PTH?

Answer 23

Increase plasma Ca2+, decrease plasma Pi

Question 24

What is the function of osteoclasts?

Answer 24

Bone reabsorption

Do not express PTH receptors

Question 25

What is the function of osteoblasts?

Answer 25

Bone formation and mineralization | High expression of PTH receptors

Question 26

What is the mechanism of PTH action?

Answer 26

- PTH stimulates macrophage colony-stimulating factor (M-CSF) in osteoblasts by binding the PTH receptor. - M-CSF stimulates differentiation of osteoclast precursors

Question 27

What is the the type of action PTH has on osteoclasts?

Answer 27

Indirect via M-CSF from the osteoblasts

Question 28

What is the effect of PTH on RANK ligand?

Answer 28

PTH stimulates RANK ligand – leads to maturation of osteoclast and bone reabsorption. Bone degradation releases Ca2+ and Pi to systemic circulation.

Question 29

What is Osteoprotegerin (OPG)?

Answer 29

It is an antagonist of RANK ligand which leads to the down regulation of osteoclasts

Question 30

How does increased cortisol lead to osteoporosis?

Answer 30

Cortisol inhibits OPG -> more bone breakdown and can lead to osteoporosis

Question 31

How does PTH affect the kidney?

Answer 31

Stimulates CYP1α – encodes 1alpha-hydroxylase

Question 32

What is the function of 1alpha-hydroxylase?

Answer 32

Converts Vitamin D into its active form

Question 33

How does the active form of Vitamin D affect the kidney?

Answer 33

Stimulates Ca2+ channel insertion in apical membrane of distal tubule

Question 34

What is the main regulator of PTH?

Answer 34

Ca concentration in the plasma

Question 35

How does the parathyroid gland detect changes in Ca?

Answer 35

CaSR - the calcium sensing receptor

Question 36

What is the function of the CaSR?

Answer 36

Located in chief cells, kidney tubules, C cells and it binds ionized Ca2+. It has 2 functions: • Inhibits PTH synthesis at promoter level • Stimulates degradation of preformed PTH

Question 37

How does Vitamin D regulate PTH?

Answer 37

Binds nuclear receptor - VDR - Inhibits PTH synthesis at promoter level - Stimulates CaSR gene transcription – indirect regulation of PTH

Question 38

What is Calciferol?

Answer 38

General term for vitamin D and other natural structural analogs.

Question 39

What is Cholecaciferol?

Answer 39

Vitamin D3 from animals

Question 40

What is Calcidiol?

Answer 40

25-D

Question 41

What is Calcitriol?

Answer 41

1,25-D (active form)

Question 42

What binds Vitamin D in the plasma?

Answer 42

Vitamin D- binding protein

Question 43

What are the targets of Vitamin D?

Answer 43

Bone Kidney Intestine

Question 44

What target of Vitamin D does PTH NOT act upon?

Answer 44

Intestine. PTH acts on the intestine via the effects of Vitamin D.

Question 45

How does Vitamin D directly affect the bone?

Answer 45

Mobilize Ca2+ from bone Osteoblasts and osteoclasts have VDRs so Vitamin D stimulates osteoclast proliferation/differentiation.

Question 46

What is an indirect effect of Vitamin D on the bone?

Answer 46

It increases the plasma Ca so it then causes bone mineralization to occur

Question 47

How does Vitamin D affect the intestine?

Answer 47

Increases transcellular Ca2+ absorption in duodenum Stimulates Pi reabsorption from small intestine

Question 48

What is osteoporosis and what causes it?

Answer 48

Reduced bone density – mainly trabecular bone Causes: genetic, menopause (low estrogen), glucocorticoid therapy/chronic stress, low dietary Ca2+

Question 49

What are the causes of hyperparathyroidism?

Answer 49

Hyperplasia, carcinoma of parathyroid gland

Question 50

What are some of the effects of hyperparathyroidism?

Answer 50

Hypercalcemia, kidney stones and renal failure which leads to reduced Vitamin D -> excess PTH synthesis.

Question 51

What is the function of bisphosphonates used in treatment of osteoporosis and what is their problem?

Answer 51

Bisphosphonates inhibit osteoclasts so that | bone cannot be broken down and it can cause hairline fractures that will not be fixed by bone cycling

Question 52

What are some of the effects of hypothyroidism?

Answer 52

Hypocalcemic tetany -> due to increased excitability of neurons

Question 53

What causes rickets in children and osteomalacia in adults?

Answer 53

Unmineralized bone due to Vitamin D deficiency

Question 54

What is pseudohypoparathyroidism?

Answer 54

Congenital defect in G protein that associates with PTHR1. It causes a generalized resistance to PTH, TSH, LH, and FSH which leads to these symptoms: - low Ca++ - high phosphate - elevated PTH - short stature

Question 55

What is the normal serum Pi level?

Answer 55

0.8-1.45 mM

Question 56

What is the role of calcitonin in Ca regulation?

Answer 56

Normal physiological importance is unclear

Question 57

What is the use for calcitonin clinically?

Answer 57

Inhibits osteoclast reabsorption of and slows bone turnover

Question 58

What is the escape phenomenon associated with calcitonin therapy that can prove problematic?

Answer 58

“Escape” phenomenon – rapid downregulation of calcitonin receptors cause the antiosteoclastic actions of calcitonin to diminish within a few hours making this a less effective treatment option.