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FHB Block 4 > L8- Parathyroid and Regulation of Calcium > Flashcards

L8- Parathyroid and Regulation of Calcium Flashcards

1
Q

Name 6 major roles of Ca2+ in the body

A

1) Membrane stability and cell function
2) neuronal transmission
3) Bone structure/formation
4) Blood coagulation
5) Muscle function
6) Hormone secretion

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2
Q

Name 5 major roles of phosphate in the body

A

1) Cellular energy metabolism (ATP)
2) Intracellular signaling pathways
3) Nucleic acid backbone
4) Bone structure
5) Enzyme activation/deactivation

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3
Q

How can we approximate free calcium availability in the blood?

A

Albumin levels

albumin levels are a good indication of free calcium availability

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4
Q

What are the two primary regulators of plasma calcium levels?

A

Parathyroid hormone (PTH) and Vitamin D/calcitriol (skin/diet)

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5
Q

What is the role of calcitonin?

A

Traditionally calcitonin was taught as the opposite regulator of PTH and Vitamin D- but it is potentially not important for humans

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6
Q

Describe the daily calcium turnvover

A

Typical dietary intake = 1000mg
50% absorbed by intestines, but 30% excreted
–> Net uptake is 200mg

Urinary excretion is about the same as GI absorption

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7
Q

Where is the parathyroid gland located?

A

Anterior surface of thyroid gland

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8
Q

What are Chief cells of the parathyroid gland responsible for?

A

Synthesis of PTH

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9
Q

What are oxyphil cells of the parathyroid gland known for?

A

No known function. They are known to increase with age

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10
Q

What is the half-life of parathyroid hormone?

A

4 minutes

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11
Q

Differentiate the N-term from the C-term of the parathyroid hormone?

A

N-term: 1-34, biologically active (binds to the PTH receptor)
C-term: 35-84, inactive, but has a longer half-life than other fragments

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12
Q

What is parathyroid hormone related peptide? How prevalent is it in the blood?

A

Peptide that mimics the action of PTH in the bone and kidney.

Normally found at very low concentrations- not a regulatory of plasma Ca2+

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13
Q

What is the source of parathyroid hormone related peptide?

A

Many tumors produce PTHrP (renal, bladder, lymphoma, head/neck) which DOES regulate Ca2+ (leads to hypercalcemia)

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14
Q

What is the primary parathyroid receptor? Where is it located?

A

PTH 1R- located in the osteoblasts and kidney (for bone reabsorption of Ca2+ from the bone and kidneys)

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15
Q

What type of protein is the parathyroid hormone receptor?

A

G-protein coupled receptor –> stimulates both cAMP and IP3/DAG depending on the coupled alphas/q protein

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16
Q

What is the relevance of parathyroid hormone receptor 2R?

A

Physiologic importance in humans is unclear- does not bind to PTHrP

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17
Q

What are the net effects of PTH binding to the PTH receptor?

A

Increase in plasma Ca2+, decrease in plasma Pi

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18
Q

Where is the majority of Ca2+ in the body located?

A

99% of Ca2+ in the body is in the bone

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19
Q

Differentiate osteoblasts from osteoclasts

A

Osteoblast: Blasts Build- responsible for bone formation and mineralization. High expression of PTH receptors

Osteoclasts: bone reabsorption- do NOT express PTH.

All PTH effects are through osteoblasts (they stimulate osteoclasts indirectly through RANKL expression)

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20
Q

The majority of the bone matrix is composed of what cells?

A

Osteocytes - cells that are terminally differentiated from osteoblasts

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21
Q

Describe how parathyroid hormone stimulates osteoclasts indirectly

A

PTH binds to osteoblasts and stimulates macrophage colony-stimulating factor (M-CSF). M-CSF stimulates differentiation of osteoclast precursors.

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

22
Q

What is the role of osteoprotegerin (OPG)?

A

OPG is an antagonist of RANK ligand. It is normally secreted by osteoblasts.

PTH binding to osteoblasts upregulates the production of M-CSF and downregulates the production of osteoprotegerin

23
Q

What two hormones affect OPG production?

A

Estrogen stimulates OPG production (protective of bone density)

Glucocorticoids inhibit OPG production

24
Q

How do osteoclasts release free calcium and phosphate from bone?

A

They secrete acid- the acid environment dissolves bone mineral and hydrolyzes bone matrix

25
Q

What happens upon binding of PTH to the PTH receptor in the kidney

A

1) PTH binds —> cAMP/PKA signaling pathway –> stimulation of CYP1 alpha gene transcription –> 1alpha-hydroxylase production –> conversion of vitamin D3 to its active form
2) PTH stimulates Ca2+ channel insertion in the apical membrane of the distal tubule and allows for greater Ca2+ reabsorption

26
Q

Where are the role of the calcium-sensing receptors (CaSR)s located?

A

CaSRs are located in the chief cells, kidney tubules and C cells (where PTH is made)

27
Q

What is the role of CaSRs?

A

They bind to ionized Ca2+ and inhibit PTH synthesis and the promoter level in addition to stimulating the degradation of preformed PTH.

28
Q

How does vitamin D regulate calcium plasma levels?

A

Vitamin D binds the VDR and inhibits PTH synthesis at the promoter level. It also stimulates CaSR gene transcription leading to indirect regulation of PTH (through an increase in the number of CaSR –> more sensitive response to Ca2+ in the plasma)

29
Q

What is calciferol?

A

General term for vitamin D and other natural structural analogs

30
Q

What is cholecalciferol?

A

Cholecalciferol specifically refers to vitamin D3 (from animal tissues)

31
Q

What is calcidiol?

A

25-hydroxy-cholecalciferol - the immediate precursor to the active form of cholecalciferol

32
Q

What is calcitriol?

A

1,25-dihydroxy-cholecalciferol, the active form of vitamin D

33
Q

What is ergocaliferol?

A

Vitamin D2- dietary vitamin D from vegetables

34
Q

How does vitamin D travel through the blood?

A

Bound to vitamin D-binding protein

35
Q

What is the role of UV light in the synthesis of active vitamin D?

A

The precursor hormone 7-deydrocholesterol is converted to cholecalciferol in the skin by UV light, and it is then isomerized to form Vitamin D3. Vitamin D3 is bound in circulation to vitamin D binding protein and transported to the liver. Bioactivation of vitamin D3 and D2 requires 1 alpha hydroxylase (in the kidney), which is stimulated by PTH.

36
Q

What is the default pathway for vitamin D synthesis?

A

The default pathway is the inactive form 24,25-(OH2)-D3. Hypocalcemia and hypophosphatemia are primary factors driving conversion to active vitamin D.

37
Q

How does vitamin D directly affect bone?

A

Vitamin D binds to both osteoblasts and osteoclasts (they both have VDRs)

Binding of the receptor leads to mobilization of Ca2+ from the bone along with osteoclast proliferation/differentiation

38
Q

What is the indirect action of increased plasma calcium?

A

Increased plasma calcium promotes bone mineralization

39
Q

How does vitamin D increase transcellular Ca2+ absorption in the duodenum?

A

Vitamin D stimulates the synthesis of TRPV5/6, calbindin and the membrane calcium ATPase pump- together they increase the absorption of Ca2+

40
Q

What is a normal serum calcium range?

A
  1. 2-2.5mM

8. 8-10.3 mg/dL

41
Q

What is a normal serum phosphate range?

A
  1. 8-1.45mM

2. 4-4.1 mg/dL

42
Q

What are treatments for osteoporosis?

A

Estrogens, calcitonin, bisphosphonates (inhibits bone resorption) and vitamin D

43
Q

What are primary causes of hyperparathyroidism?

A

Hyperplasia or carcinoma of parathyroid gland

44
Q

What are symptoms of hyperparathyroidism?

A

kidney stones

45
Q

What are causes of secondary hyperparathyroidism?

A

Renal failure –> reduced vitamin D leads to excess PTH synthesis

46
Q

What are symptoms of hypoparathyroidism?

A

Hypocalcemic tetany

47
Q

What is the Chvostek sign?

A

twitching of facial muscles in response to tapping of the facial nerve

48
Q

Rickets/Osteomalacia are caused by what deficiency?

A

Vitamin D

49
Q

What cells produce calcitonin?

A

C cells of the thyroid gland

50
Q

What is calcitonin used for? What disease is it used to treat?

A

Calcitonin is used therapeutically for the inhibition of osteoclast resorption of calcium and slows bone turnover

Calcitonin is used to treat Paget disease (localized regions of excessive bone resorption and reactive sclerosis)

FHB Block 4 (15 decks)

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