Vitamin D and Calcium Flashcards

1
Q

What are the three sites of extracellular fluid interface for calcium exchange?

A

The intestine, the bone (acts as a reservoir of Ca), and the renal tubule

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2
Q

What are the three main regulators of calcium levels?

A

Vitamin D, parathyroid hormone (these are the main two), also calcitonin

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3
Q

How much of the total body calcium is in the extracellular fluid, and where is most of it stored?

A

only 1%, most is stored in the bone

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4
Q

What are some of the functions that require appropriate calcium levels?

A

excitation/contraction of heart and muscles, synapses, platelet aggregation, coagulation, secretion of hormones by exocytosis

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5
Q

Where are calcium levels higher: extracellular or intracellular?

A

They are higher extracellularly. There is 10,000 X less ca inside than outside the cell

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6
Q

What maintains the concentration difference of calcium between the intracellular and extracellular environments?

A

Na/Ca exchangers and ATP dependent ca pumps

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7
Q

What are the two ways that Ca can enter the cell?

A

Either from the extracellular environment through receptor or voltage gated Na channels, or it is released from internal stores from endoplasmic reticulum or mitochondria (IP3) signaling

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8
Q

What happens if the parathyroid is removed?

A

Get severe hypocalcemia, tetany, and death

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9
Q

How does space flight induce bone loss?

A

Loss of gravity leads to loss of parafollicular cells (thyroid C cells), which means that no calcitonin is made, inducing bone loss

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10
Q

What diseases can calcitonin be used to treat?

A

Lytic Paget’s disease, hypercalcemia, and osteoporosis

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11
Q

Where are vitamin D receptors present?

A

bone, kidney, intestines, but also in other cells like immune cells, testis and breast (have a role in cancer)

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12
Q

Explain the differentiation process of bone cells.

A
  1. CFU-GM cells are stimulated by CSF (colony stimulating factor) to differentiate into promonocytes
  2. When the promonocyte is stimulated with osteoclast activating factors (OAFs) and transforming growth factor alpha (TGFa, cytokine) –> formation of early preosteoclasts, which are similar to macrophages
  3. PTH and 1,25D cause differentiation of preosteoclasts into late preosteoclasts
  4. Further stimulation by PTH and 1,25D leads to formation of osteoclasts (now there is downregulation of PTH and 1,25D receptors, and receptors for calcitonin)
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13
Q

What is a mature osteoclast, and what is its function?

A

It is a bone resorption cell that moves to the bone surface and secretes acids and enzymes to break down bone in the bone remodelling cycle.

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14
Q

What type of receptors do mature osteoclasts have?

A

Have receptors for calcitonin, but not for vitD or PTH

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15
Q

What is an osteoblast?

A

It is a bone forming cell that secretes the bone matrix, also derived from bone marrow

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16
Q

What type of receptors do osteoblasts have?

A

They have receptors for PTH and Vit D.

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17
Q

What are bone cells and immune cells derived from?

A

Bone marrow

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18
Q

Explain the bone cycle

A
  1. Osteoclasts dig a hole in the resting bone surface
  2. Macrophages mop up debris
  3. Osteoblasts are recruited to the hole that was made by the osteoclasts
  4. Osteoblasts secrete bone matrix
  5. Three is calcification and mineralization, formation of crystals of hydroxyapatite and collagen
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19
Q

How long does the bone cycle take?

A

approximately 6 months

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20
Q

What are the 3 tissues that vitamin D is made in?

A

Liver, kidneys, skin

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21
Q

Where is calcitonin made?

A

parafollicular cells (C cells) in the thyroid gland

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22
Q

Where is parathyroid hormone made?

A

In parathyroid cells of parathyroid gland

23
Q

What is majority of vit D made from?

A

Make around 90% from a metabolite of cholesterol that is present in the skin when exposed to UV light, then is further processed in the liver and kidney

24
Q

What are some of the key functions of vitamin D?

A

Formation of normal bones and teeth by maintaining proper blood calcium levels and phosphate ions. Cell differentiation and development

25
Q

What type of hormone is vitamin D?

A

A secosteroid hormone

26
Q

What is the reaction that results in vitamin D synthesis in the skin?

A

7-dehydrocholesterol –> preD3 by UV rays –> cholecalciferol (type of D3) through heat

27
Q

What wavelength of light do you need to produce vitamin D?

A

295 nanometers

28
Q

What type of receptor does vitamin D bind to?

A

Binds to the same type of high affinity nuclear receptor as steroids –> not a vitamin in this sense

29
Q

Are the nuclear receptors for VitD bound by HSP?

A

No

30
Q

How is the concentration of vitamin D upregulated?

A

low phosphate levels, low calcium ions, low vitamin D, and high PTH

31
Q

How is vitD concentration downregulated?

A

High vitD inhibits its own vitD receptor transcription and upregulates hydroxylase that will break down vitD –> faster breakdown and reduced receptors (since it is not a protein you cannot alter its transcription)

32
Q

Explain the process of vitamin D transport and metabolism from the liver to the kidneys

A
  1. D3 and D2 are transported by specific vit D transport proteins to the liver, where it is oxidized by cytochrome p450 enzymes
  2. 25OHD3 is transported to the kidneys by a non-specific globulin transport protein, where another cp450 oxidase enzyme converts
    2b. Can store the vitamin D precursor in liver and fat (24, 25(OH)2D3 = inactive form), until needed. Then when there is low phosphate, low calcium, and high PTH –> favour of 1,25(OH)2D calcitriol = active form (1,25OH2D3)
  3. A hydroxylase deactivates vitamin D in the liver and kidneys
33
Q

When is production of calcitriol favoured, and when is storage of inactive form favoured?

A

When there is low phosphate, low calcium, and high PTH, you will get formation of active form. When there is high phosphate, high calcium, and high vitamin D you will get storage of inactive form (24,25(OH)2D3

34
Q

What is the rate limiting step of vitamin D metabolism?

A

Conversion into calcitriol in the kidneys

35
Q

What is the general action of vitamin D on the VDR?

A

Vit D receptor forms a heterodimer with retinoic X receptor, and is bound to the VDRE in the DNA to affect transcription and cell differentiation/development, and maintaining normal blood levels of Ca and phosphate.

36
Q

How does vitamin D promote calcium ion uptake from the intestine?

A
  1. Calcitriol diffuses across the membrane of intestine cells
  2. C binds to VDR as a dimer with RXR
  3. This upregulates mRNA for genes like Ca channels, calcium binding protein, and vitD receptor
  4. Ca ion transported from lumen across calcium channel, then binds to CBP and transporters, which are moved across the intestinal cells
  5. Ca ion is released into the blood/extracellular fluid by calcium channels, saved from excretion
37
Q

What does VitD increase transcription of?

A

Ca channels, calcium binding protein, vit D receptor, and osteocalcin (important for bone formation)

38
Q

What is the effect of vitD on PTH?

A

It decreases PTH, which helps keep Ca and phsphate in bond (PTH causes ca release from bone to blood plasma)

39
Q

What is the effect of vitD on differentiation?

A

Differentiation of hematopoetic, epidermal, hair follicle, and osteoblast and osteoclast cells –> vitamin D is an antiproliferation and prodifferentiation signal

40
Q

What is RANKL expression increased by?

A

Both vitamin D and PTH, increased expression in osteoblasts which stimulates formation and activation of osteoclasts

41
Q

What type of hormone is parathyroid hormone?

A

a peptide hormone, so it can be regulated by transcription, proteolytic processing, and vesicular secretion

42
Q

How does PTH affect Ca levels through the kidneys (what receptor type does it act on, etc.)?

A

PTH uses a GPCR g alpha q –> PLC –> IP3 and DAG –> Ca channels open and uptake from urinary tract to increase plasma Ca

43
Q

How does PTH affect calcium levels through the bone?

A

Indirectly stimulates osteoclasts, which cause bone resorption and release of Ca

44
Q

How does PTH affect Ca levels through the intestine?

A

Increases absorption of Ca indirectly through upregulation of active vit D –> no PTH receptor in intestine but PTH increases vit D activation in the kidneys –> inc Ca uptake

45
Q

How is PTH synthesized?

A

Synthesized in parathyroid cells. PTH is sensitive to Ca and senses Ca through a extracellular ca ion sensor receptor (CaR). Get PTH gene expression in the nucleus

46
Q

How does increased Ca ions inhibit PTH synthesis?

A

Parathyroid cells have a CaR that senses calcium levels –> get influx of Calcium, which directly inhibits nucleus PTH gene expression

47
Q

What type of receptor is the CaR?

A

GPCR (aq) –> PLC –> IP3 DAG –> Inc Ca = inhibition of PTH synthesis and sexretion

48
Q

What acts as the secretion signal after stimulus for PTH?

A

Intracellular magnesium

49
Q

What stimulates the release of PTH?

A

Hypocalcemia

50
Q

What receptor type does calcitonin bind to?

A

A GPCR (Gas) –> AC –> cAMP

51
Q

Where are calcitonin receptors located?

A

Osteoclasts and kidney tubules

52
Q

What type of hormone is calcitonin?

A

A peptide hormone

53
Q

What are the main effects of calcitonin?

A
  1. Inhibits osteoclasts –> lowers blood Ca (main effect)
  2. Inhibits Ca resorption from the gut –> lowers blood Ca indirectly (no calcitonin receptors in the gut)
  3. Also promotes deposition of calcium into bones
  4. Inhibits Ca reabsorption
54
Q

What signals calcitonin release from the parafollicular cells?

A

They have a CaR, Ca2+ detection by CaR leads to secretion of calcitonin