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FHB Exam 4: Endocrinology and Reproduction > Endocrine VI: Parathyroid and Calcium Regulation > Flashcards

Endocrine VI: Parathyroid and Calcium Regulation Flashcards

1
Q

What is calcium important for physiologically?

A
  • membrane stability and cell function
  • neuronal transmission
  • bone structure/formation
  • blood coagulation
  • muscle function
  • hormone secretion
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2
Q

What is phosphate important for physiologically?

A
  • cellular energy metabolism (ATP)
  • IC signaling
  • nucleic acid backbone
  • bone structure
  • enzyme activation/deactivation
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3
Q

What are the 2 primary regulators of calcium?

A

1) PTH (main one)

2) vitamin D/calcitriol (skin, diet)

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4
Q

Which cells are responsible for synthesizing PTH?

A

chief cells (also called principal cells)

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5
Q

Is PTH stimulation of osteoclasts direct or indirect?

A

indirect (must go through osteoblast)

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6
Q

What is the primary receptor for PTH?

A

PTH 1R (located in osteoblasts and kidney, GPCR, binds 1-34 fragment, 1-84, and PTHrP)

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7
Q

Is there more phosphate or calcium in soft tissue?

A

Phosphate (10-fold more)! A severe tissue “crush” injury can actually result in hyperphosphatemia.

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8
Q

How much calcium in the plasma is in the free/ionized form?

A

50% (45% is protein-bound, usually to albumin, and then remainder is complexed to various anions in the plasma)

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9
Q

How does acidemia affect free calcium in the plasma?

A

Acidemia will result in an increased concentration of ionized calcium because there are less binding sites on albumin (negatively charged) available for calcium, as many of the binding sites are occupied by H+. If calcium cannot be complexed with albumin, then there will be more free/ionized calcium in plasma.

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10
Q

What is the function of bioactive vitamin D (calcitriol)?

A

It is responsible for increasing the body’s calcium pool, through absorption of calcium from intestine, inhibition of calcium excretion in urine, and resorption of calcium from bone.

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11
Q

Which part of the PTH preprohormone is biologically active and binds the PTH receptor?

A

the 1-34 fragment (N-terminal fragment)

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12
Q

What is the significance of the 1-84 fragment of PTH?

A

It is a useful clinical determinant of the biologically active form of PTH. It has a half-life of 4 minutes.

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13
Q

What is PTHrP and why is it important?

A

Parathyroid hormone-related peptide is highly homologous to PTH 1-34 AA and mimics the action of PTH in the bone and kidney. It is not a regulator of plasma calcium, but it has local paracrine effects that mimic PTH. It is occasionally secreted by certain tumors (renal, bladder, lymphoma, head/neck) and results in hypercalcemia.

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14
Q

What are the PTH receptors we discussed?

A

1) PTH 1R - primary receptor, GPCR, located in osteoblasts and kidney, binds 1-34 and 1-84 fragments of PTH, as well as PTHrP
2) PTH 2R - binds 1-34 fragment of PTH but NOT PTHrP, physiological importance unclear

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15
Q

What is the net effect of PTH?

A

to increase plasma calcium and decrease plasma phosphate

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16
Q

Where is most of the body’s calcium content?

A

99% is in bone

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17
Q

Are there PTH receptors on osteoclasts and osteoblasts?

A

PTH receptors are on osteoclasts but NOT osteoblasts.

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18
Q

What is an osteocyte?

A

It is a bone cell formed when an osteoblast becomes embedded in the matrix it has secreted. Osteocytes make up most of the bone matrix and are terminally differentiated from osteoblasts.

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19
Q

What is the significance of M-CSF in bone remodeling?

A

PTH stimulates M-CSF in osteoblasts, and M-CSF in turn stimulates differentiation of osteoclast precursors. So, PTH stimulation of osteoclasts is INDIRECT and happens through stimulation of osteoblasts by M-CSF.

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20
Q

What is the significance of RANK ligand in bone remodeling?

A

PTH stimulates RANK ligand, which leads to maturation of osteoclasts and bone resorption. Bone degradation then releases calcium and phosphate into the systemic circulation.

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21
Q

_______ export __________ into the extracellular space for bone mineralization.

A

osteoblasts; calcium and phosphate

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22
Q

What is the antagonist of RANK ligand, and what is its significance?

A

OPG (osteoprotegerin) - it binds up RANK ligand and prevents bone breakdown

23
Q

Why do osteoblasts produce both RANK ligand and OPG

A

to promote bone homeostasis

24
Q

How is OPG regulated?

A
  • produced by osteoblasts
  • stimulated by estrogens (this is why estrogen is protective of bone density)
  • inhibited by cortisol
25
Q

What does PTH target in the kidney?

A

1) stimulates CYP1alpha, which encodes 1alpha-hydroxylase that converts active form of vitamin D
2) stimulates calcium channel insertion in apical membrane of distal tubule

26
Q

How is PTH regulated?

A

It is primarily dependent upon plasma calcium concentration. The higher the free calcium in blood, the lower the serum PTH.

27
Q

Where are calcium-sensing receptors (CaSR) located?

A

chief cells, kidney tubules, C cells

28
Q

What is the function of CaSRs in PTH regulation?

A

CaSRs can sense how much calcium is in the blood, which in turn affects the stimulation or inhibition of PTH production.

29
Q

What is the nuclear receptor for vitamin D?

A

VDR

30
Q

How does vitamin D regulate PTH directly and indirectly?

A
  • Directly: inhibits PTH synthesis at promoter level

- Indirectly: stimulates CaSR gene transcription

31
Q

What are the 2 main effects of the signaling pathways activated by CaSRs?

A

1) Direct inhibition of PTH gene promoter to inhibit transcription
2) Degradation of stored TH inside the cell. Degraded products are then secreted into the blood.

32
Q

What is the active form of vitamin D?

A

1,25-dihydroxycholecalciferol (aka, calcitriol or calcifitriol)
*calcidiol (calcifidiol) is the immediate inactive precursor

33
Q

What does the term “calciferol” refer to?

A

general term for vitamin D and other natural structural analogs

34
Q

Which form of vitamin D is from animal products and which is from vegetables?

A
  • vitamin D3 (cholecalciferol) is from animal tissues

- vitamin D2 (ergocalciferol) is from vegetables

35
Q

How is vitamin D carried in plasma?

A

bound to vitamin D binding protein

36
Q

What is the enzyme that converts calcidiol to the active form of vitamin D?

A

1alpha-hydroxylase (cyp450 enzyme)

37
Q

What is required to stimulate the initial activation of vitamin D?

A

UV light! This is why lack of sun exposure can lead to vitamin D deficiency.

38
Q

What are the main targets of vitamin D?

A

intestine, bone, and kidneys

39
Q

How does vitamin D affect intestinal calcium and phosphate?

A

It increases transcellular calcium absorption in the duodenum and stimulates phosphate reabsorption from the small intestine.

40
Q

What is the action of vitamin D and PTH in terms of phosphate homeostasis?

A

Vitamin D stimulates phosphate reabsorption from the small intestine, while PTH stimulates phosphate excretion by reducing reabsorption from the small intestine and kidney tubules kidney tubules. Thus, Vitamin D and PTH have opposite effects on phosphate.

41
Q

What are the direct and indirect effects of vitamin D on bone?

A
  • Direct: mobilizes calcium from bone

- Indirect: increases plasma calcium, which promotes bone mineralization

42
Q

Which hormone is the main responder to low serum calcium vs. low serum phosphate?

A

PTH responds to low serum calcium, while vitamin D responds to low serum phosphate

43
Q

What happens to calcium and phosphate levels with vitamin D deficiency?

A

Vitamin D deficiency leads to decreased GI absorption of calcium and phosphate, triggering an increase in PTH. This increases bone resorption to increase plasma and calcium and phosphate concentration. HOWEVER, an increase in PTH also causes increased phosphate excretion. Thus, a Vitamin D deficiency can cause hypophosphatemia and poor bone mineralization.

44
Q

Vitamin D deficiency is linked to which conditions?

A
  • MS
  • asthma
  • CVD
  • type II diabetes
  • colorectal and breast cancer
45
Q

What are the effects of vitamin D on the intestines, bone, immune cells, and tumor microenvt?

A
  • intestines: increases absorption of calcium and phosphate
  • bone: increases mineralization
  • immune cells: induces differentiation
  • tumor microenvt: inhibits proliferation and angiogenesis, induces differentiation
46
Q

Where does calcitonin come from?

A

32 aa peptide produced in C-cells of thyroid gland

47
Q

What are the therapeutic uses of calcitonin?

A

inhibits osteoclast reabsorption and slows bone turnover (net effect=hypocalcemic action); used to treat Paget disease

48
Q

What is the downside of using calcitonin as a treatment option?

A

“escape phenomenon” - rapid downregulation of calcitonin receptors causes antiosteoclastic actions of calcitonin to diminish within a few hours

49
Q

What are the normal ranges for serum [Ca2+] and [phosphate]?

A

- [phosphate]: 0.8-1.45 mM

50
Q

Rickets/osteomalacia is caused by what?

A

vitamin D deficiency leading to unmineralized bone

51
Q

What does hypoparathyroidism cause?

A
  • Hypocalcemic tetany

- Chvostek sign: twitching of facial muscles in response to tapping facial nerve

52
Q

What is the major treatment being used for osteoporosis?

A

bisphosphonates, which inhibit bone resorption (downside: may increase risk of fractures because mess with normal bone turnover)
*other treatments include estrogen, calcitonin, and vitamin D

53
Q

Explain primary vs. secondary hyperparathyroidism.

A
  • primary: caused by hyperplasia or carcinoma of parathyroid gland; leads to hypercalcemia or kidney stones
  • secondary: due to chronic renal failure; decreased vitamin D leads to excess PTH synthesis

FHB Exam 4: Endocrinology and Reproduction (14 decks)

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