Calcium Regulation: Parathyroid (PTH), Vitamin D, Calcitonin and Bone Disease

Question 1

what are the 3 sites of extracellular fluid interface for calcium exchange

Answer 1

•the intestine, the bone and the renal tubule (kidney) -> mainly regulated by vitamin D and parathyroid hormone and also calcitonin

Question 2

why is calcium so important?

Answer 2

Proper function of many tissues requires appropriate extracellular calcium:
•excitation / contraction of heart and muscles
•synapse and other nervous system function
•platelet aggregation and coagulation
•secretion of hormones (e.g. insulin) and other regulators by exocytosis

Question 3

what occurs if the parathyroid gland is removed?

Answer 3

•if the parathyroid gland is removed where the parathyroid hormone is made you get severe hypocalcaemia, tetany (involuntary muscle contraction) and death

Question 4

what occurs if perifollicular cells are removed

Answer 4

•if perifollicular cells are removed (aka thyroid C cells) so NO calcitonin is made or have a tumor with excess calcitonin either way there is no real disease – but we can use calcitonin to treat Lytic Paget’s Disease, hypercalcemia and osteoporosis

Question 5

Vitamin D receptors

• where are they located
• what are they important for

Answer 5

•Vitamin D receptors in the bone, kidney and intestine but also others like immune cells, testis and breast = important implications for cancer (cells response to vitamin D = antiproliferation) vitamin D also important for hormone synthesis and secretion (e.g. insulin, PTH and cytokines) regulates genes via a nuclear receptor similar to the steroid receptors

Question 6

what are macrophages

Answer 6

“mops” of immune system but also critical role in bone remodelling

Question 7

what are osteoblasts and what do they stimulate

Answer 7

• Osteoblast = bone forming cell – secretes bone matrix and has receptors for PTH and vitamin D
• Osteoblast stimulates osteoclasts

Question 8

mature osteoclast

Answer 8

•Mature osteoclast = bone reabsorption cell moves to bone surface and secretes acid and enzymes to break down bone in the bone remodelling cycle – inhibited by calcitonin –> mature cell does not divide and has receptor for calcitonin but NOT for vitamin D or PTH

Question 9

where are the following made

1. calcitonin
2. parathyroid hormone
3. vitamin D

Answer 9

1. perifolicular cells in the thyroid gland
2. in parathyroid cells
3. in combination of skin, liver and kidney

Question 10

Parathyroid Hormone

Answer 10

•Is a peptide hormone (regulation by transcription, proteolytic processing and vesicular secretion) – made in parathyroid cells of the parathyroid gland

Question 11

kidney calcium

Answer 11

•PTH uses a GPCR where Gaq PLC IP3 + DAG that signals calcium channels to open and uptake from urinary tract and increase plasma calcium

Question 12

bone calcium

Answer 12

•stimulates osteoclasts (indirectly) causing bone reabsorption such that bone releases calcium

Question 13

intestine calcium

Answer 13

•increases absorption of calcium indirectly via upregulation of active vitamin D – no PTH receptor in intestine but increases vitamin D activation in kidney thus increasing body’s calcium uptake from food

Question 14

are parathyroid cells sensitive to calcium concentration?

Answer 14

very sensitive to calcium concentration – controlled by extracellular calcium ion sensory receptor (CaR) increase in ion flux into cell INHIBITS PTH synthesis and release from secretory granules
*as calcium increases PTH decreases

Question 15

calcitonin effects (4)

Answer 15

• Inhibits calcium reabsorption in the kidney (excreted in the urine)
• Promotes deposition of calcium into bones (inhibits osteoclasts and stimulates osteoblasts)
• Inhibits calcium absorption by the intestines
• Lowers calcium levels in the blood

Question 16

what diseases is calcitonin used for in humans

Answer 16

therapeutic for Paget’s disease, hypercalcemia and osteoporosis

Question 17

where is calcitonin secreted from?

Answer 17

•parafollicular cells aka thyroid C cells regulated by same CaR found on parathyroid gland but in this case, calcium leads to secretion (not inhibition like PTH)

Question 18

what is the main effect of calcitonin

Answer 18

Inhibits osteoclasts (bone reabsorption) so lowers blood calcium

Question 19

what is the secondary effect of calcitonin

Answer 19

Inhibits calcium absorption from gut so lowers blood calcium (indirectly as no receptors for calcitonin here)

Question 20

what is vitamin D essential for?

Answer 20

the formation of normal bones and teeth by maintaining normal blood levels of calcium ions and phosphate ions but also many important effects including cell differentiation and development

Question 21

what is calcitrol

Answer 21

active vitamin D hormone which is one of the forms of D3

Question 22

why do we discuss vitamin D as a hormone and less so as a vitamin

Answer 22

because we make most of it (~90%) from a metabolite of cholesterol that is present in the skin when exposed to UV light and then is further processed in the liver and kidney

Question 23

vitamin D structure

Answer 23

related to steroids and not a vitamin in this context because uses the same type of high affinity nuclear receptor to affect transcription as steroids, and levels regulated (as compared to a vitamin that is typically from diet and is a cofactor for some protein or enzyme to assist in its function)

Question 24

where are vitamin D receptors

Answer 24

the bone, kidney and gut but also others like immune cells, testis and breast – important implications for cancer (vitamin D signals antiproliferation)

Question 25

what is the concentration of vitamin D up regulated by

Answer 25

low phosphate, low calcium ions, low vitamin and high parathyroid hormone
- if high vitamin D feedback inhibits own vitamin D receptor transcription and upregulates hydroxylase that will breakdown vitamin D

Question 26

General vitamin D action on nuclear receptors

Answer 26

Vitamin D receptor (VDR) forms heterodimer with retinoic x receptor (RXR) on vitamin D response element (VDRE) on the DNA to affect transcription and production of proteins for cell differentiation and development (anti-proliferation role in cancer) and maintaining normal blood levels of calcium ions and phosphate

Question 27

specific examples of vitamin D action on nuclear receptors

Answer 27

increase calcium channels in intestine and brings calcium into cell plus in same cells increase calcium-binding protein (calbindin transports calcium in cytosol); many cell types increases vitamin D receptor; in bone cells increase osteocalcin (bone formation protein); also decrease parathyroid hormone synthesis in parathyroid cells. The transcripts that are affected will depend on which cell type

Question 28

calcium ion uptake in intestines promoted by vitamin D (5 steps)

Answer 28

1. Calcitriol = C aka Vitamin D diffuses across the membrane
2. Binds VDR in nucleus as dimer with RXR
3. Upregulates mRNA for genes like calcium channels, calcium-binding protein (CBP) and vitamin D receptor
4. Calcium ion transported from lumen across calcium channel, then binds CBP and transporters and moved across intestinal cells
5. Calcium ion released into blood or fluid between cells in the intestine – saved from excretion path

Question 29

vitamin D action with bone formation (4 points)

Answer 29

• Increase transcription of calcium channels, calcium-binding protein, vitamin D receptor also osteocalcin which is an important protein for bone formation
• decrease parathyroid hormone which helps keep calcium and phosphate in bone (recall PT causes calcium release from bone to blood plasma)
• differentiation of hemapoetic, epidermal, hair follicle, osteoblast and osteoclast cells
• want osteoblast and osteoclast balance

Question 30

Hypercalemia

Answer 30

too much calcium

Question 31

what can cause hypercalemia (4)

Answer 31

• hyperparathyroidism (e.g. tumor)
• increased bone reabsorption freeing calcium (hormone imbalance)
• increase gut absorption of calcium (hormone imbalance)
• decreased kidney excretion, retaining calcium (hormone imbalance & kidney damage)

Question 32

hyperparathyroid disease

Answer 32

• Hyperparathyroid causes hypercalcemia and many symptoms – could be from a tumor and is often associated with hyperthyroidism
• Calcium levels suppress PTH transcription and secretion normally but here PTH is out of control increasing serum calcium more

Question 33

what is used to treat hyperparathyroid disease

Answer 33

Calcitonin to treat (intravenously) causes rapid decline of serum calcium and phosphate through actions on bone – calcitonin acts faster than PTH so prevents hypercalcemia

Question 34

what is the most common reasonfor hypercalemia

Answer 34

most commonly due to overactive parathyroid glands – too much calcium in your blood can weaken your bones, create kidney stones and interfere with how your heart and brain work

Question 35

Rickets disease

Answer 35

occurs in children (bones growing i.e. not fused)
•Lack vitamin D causes decrease in calcium and phosphate which results in secondary hyperparathyroidism (PTH too high) and increased bone reabsorption

Question 36

physical effects of Rickets

Answer 36

bow legs and humpbacks (in children)

Question 37

osteomalacia

Answer 37

Occurs in adults - fused bone
•Mineralization of newly formed bone matrix is defective – lack vitamin D, low calcium or low phosphate can cause Osteomalacia in adults with fused bone associated with osteoporosis

Question 38

vitamin D deficiency - type 1

Answer 38

lack of vitamin D - could be due to environment or genetic defect – especially defective enzyme needed for synthesis or culture/religion or someone too sick to go out

Question 39

vitamin D deficiency - type 2

Answer 39

•normal vitamin D levels but insensitive due to defect in receptor - called alopecia

Question 40

vitamin D excess

Answer 40

•Excessive sun exposure does not result in vitamin D toxicity because sustained heat on the skin photodegrades plus nonactive products formed – long-term intakes above the upper limit of 4000IU increase risk of vitamin D toxicity

Question 41

Lytic Paget’s Disease (aka Osteitis Deformans)

Answer 41

• Characterized by rapid bone loss because of accelerated bone turnover- rate of bone reabsorption / depredation is too high
• Associated with osteoarthritis
• Calcitonin to treat

Question 42

Renal secondary hyperparathyroidism

Answer 42

• Kidney deterioration causes vitamin D problem – phosphate retention that downregulates vitamin D and also can’t make as much vitamin D in damaged kidney
• So decrease in calcium in a viscous circle causing more parathyroid hormone (since calcium inhibits)

Question 43

what is osteoperosis

Answer 43

A disorder of the bones in which the bones become brittle weak and easily damaged or broken. A decrease in the mineralization and strength of the bones overtime causes this.

Question 44

treatment of osteoperosis

Answer 44

•Calcitonin or hormone therapy may be used to treat but healthy diet and exercise most important

Question 45

what can osteoperosis result from

Answer 45

• low estrogen and high glucocorticoids associated with osteoporosis (uncoupling bone formation and resorption cycles)
• can result from long-term vitamin D insufficiency because decreased calcium absorption – smoking and alcohol contribute to bone loss

Question 46

what hormones mainly affect bones

Answer 46

•hormones affect bones – vitamin D and parathyroid hormone especially but also estrogen, testosterone, glucocorticoids and others

• estrogen acts on osteoclasts and osteoblasts to inhibit bone breakdown
• testosterone important for skeletal growth
• glucocorticoid excess contributes to bone loss

Question 47

what cells have receptors for calcitonin

Answer 47

osteoclasts