Parathyroid - Manautou

The parathyroid gland is responsible for the synthesis and release of which hormone?

The parathyroid gland is responsible for the synthesis and release of which hormone?

PTH;parathyroid hormone

PTH is a important regulator of__________

calcium homeostasis and phosphate homeostasis

What is the main effect of PTH

Increase the plasma levels of calcium by affecting the target organs

PTH affects which target organs?

bone, kidneys, intestine

What are the 2 functions of PTH

1. increase Ca2+ within the plasma

2. stimulates renal phosphate elimination

What happens if PT has a surgical removal of the parathyroid gland and only one is remaining? What is the outcome of the single parathyroid?

Then the single parathyroid gland will grow in size and try to produce enough PTH to compensate the 3 that were originally producing PTH

What cells are the main source for PTH?

Chief cells

What are 2 cell types that exist within the parathyroid gland

1. chief cells

2. oxyphil cells

Explain the regulation and synthesis of PTH

• The parathyroid gland senses ionized Ca2+ and produces PTH when there are levels of Ca2+

  • Low Ca2+ (ionized) → parathyroid gland → chief cells → PTH produced

What type of receptor does Ca2+ bind to in the Chief cells?

GPCR

When ________ or _______ Ca2+ present, PTH is inhibited.

high, sufficient

When ______ Ca2+ present, PTH secretion is activated.

low

What type of relationship does PTH secretion have with plasma Ca2+?

• inverse correlation

• HIGH Ca2+ = DECREASE PTH secretion

• LOW Ca2+ = INCREASE PTH secretion

PTH-receptor are coupled to which 2 different classes of G protein?

Gs and Gq; G stimulatory protein and G q protein

What are the effects of PTH?

• Causes hyperplasia of osteoclasts

• Binds to osteoblasts receptors to increase cAMP and PLC

• The signal transduction will increase osteoclast activity and acid secretion and acid secretion from osteoclasts

• Stimulate biosynthesis of 1-25-dihydroxy vitamin D3 by the kidneys 5) Enhances intestinal uptake of calcium

• Increases phosphate excretion across the proximal tubule

• Increases renal distal tubule reabsorption of calcium

T/F Osteoblast and osteoclasts have receptors for PTH

False, osteoblasts have receptors for PTH but osteoclasts do not

• osteoclasts receive signaling from osteoblasts via paracrine signaling (RANKL)

How does PTH affect the kidneys?

1. PTH increases calcium reabsorption in the distal nephron

2. Calcium channels are inserted into the apical membrane to increase reabsorption via cAMP-and PKA-dependent process

3. In proximal tubules phosphate reabsorption is inhibited by removal of sodium-phosphate co-transporters from luminal membrane

4. 1,25 (OH)2D3 (Vitamin D) synthesis by kidney increases in response to PTH

Contrast the difference between osteoclasts and osteoblasts

Osteoclasts: Breaks down bone and promotes bone resorption Osteoblasts: mediates bone formation

What regulates the coordinates of the function of osteoblasts and osteoclasts?

PTH

What is the importance of the osteocytic membrane?

The importance of the osteocytic membrane is that it is an important source of calcium for rapid correction of plasma calcium. The importance is when PTH is present, calcium is able to move from the bone into the bloodstream after passing the osteocytic membrane

What are the two stages of Ca2+ blood levels in plasma used to try to correct the Ca2+ levels within the body?

1. fast exchange

   1. Osteocytic membrane pumps Ca2+ out from the bone fluid that’s available once it’s depleted

2. slow exchange

   1. in use once the fast exchange is depleted, the osteoclasts begin chewing on the bone to release more Ca2+

Where can you get sources of vitamin D?

Skin and diet

At which position does the 1st hydroxylation occur for vitamin D?

position 25 at Liver

At which position does the 2nd hydroxylation occur for vitamin D?

position 1 at Kidney

Which hydroxylation step is regulated by PTH?

Hydroxylation at position 1 in Kidney

When is Vitamin D in its fully activated form?

After undergoing 2nd hydroxylation step in position 1 at the kidney

What is the mechanism of vitamin D?

Binds to the nuclear receptor and works as a transcription factor

What are 2 target organs Vitamin D acts on to increase the Ca2+ concentration in plasma (calcium homeostasis)?

intestine and bone

What affect does vitamin D have on intestine for calcium homeostasis?

increase the synthesis and function of calbidins (calcium binding proteins)

What affect does vitamin D have on bones for calcium homeostasis?

increase the activity of osteoclasts

What happens if you have high active form of vitamin D?

Feedback inhibition will repress the synthesis and release of PTH secretion

Smaller quantities of vitamin D under normal plasma calcium concentrations will promote what?

bone calcification (bone formation)

Name the 2 mechanisms for the calcium binding protein (calbidins)

1. uptake of Ca2+ to blood

2. Transcellular transport

3. Endocytosis and exocytosis of Ca2+

Where is calcitonin produced?

Parafollicular cells in thyroid gland

What are the 2 peptides calcitonin gene encodes for?

Calcitonin and CGRP

If you have complete removal of the thyroid gland and you don’t have any parafollicular cells what do you think it will do the Ca2+ levels in humans?

Nothing, no excess of Calcitonin is associated with any disease but you may have difficulty processing high Ca2+

[just takes longer to process]

When is calcitonin released?

When Ca2+ levels are high in the blood it will lower it

What are the 4 functions of calcitonin?

1. Suppresses activity of osteoclasts

2. Causes osteoclasts to lose “ruffled border”

3. Inhibits the formation of citric and lactic acid

4. Release of proteolytic enzymes that destroy the bone matric is inhibited

Describe the symptoms of PRIMARY hyperparathyroidism.

results in excessive secretion of PTH due to the enlargement glands and tumors

What is the consequence if PT has primary hyperparathyroidism?

Hypercalcemia/hypophosphatemia

• too much phosphate will be eliminated via renal

Describe secondary hyperparathyroidism

PTH is also elevated but it is NOT associated with hypercalcemia it is associated with deficiency in vitamin D synthesis and/or its action

What is the difference between primary and secondary hyperparathyroidism?

primary: results from excessive PTH because of enlargement of glands/tumors

secondary: PTH elevated because of low levels of Ca2+ but associated with deficiency of vitamin D synthesis

What are 2 ways to get hypoparathyroidism

1. idiopathic - absence of PTH (from the autoimmune or surgical removal of the thyroid gland)

2. pseudohypoparathyroidism (target tissues resistant to PTH, but the right amount of PTH is made)

   1. could be associated with genetic deficiency in cAMP or defective GPCR

What are the symptoms of Hypoparathyroidism

muscle cramps, muscle spasms (tetany)

Ergocalciferol

pure Vitamin D2

• for PT’s with normal liver and kidney

Dihydroxytachysterol

doesn’t require renal activation

Calcifediol

requires renal activation

• works for PTs that have liver impairment BUT their renal works fine (already bioactivated at position 25)

Calcitrol

full active form on vitamin D

• acts very quickly, very expensive

• works for PTs with liver and renal impairment and PTs with low levels of Ca2+

What are bisphosphonates?

analogs of pyrophosphate that inhibit bone resoprtion`

What is the MOA of bisphosphonates?

• Bisphosphonates target FPPS which is the major enzyme target. It also covalently attaches to lipids to form a protein prenylation

Which enzyme does the bisphosphonate target to prevent protein prenylation?

Farnesyl pyrophosphate synthase; FPPS

What is the outcome after bisphosphonates block FPPS?

osteoclast will undergo apoptosis

Contrast how persistent exposure to synthetic PTH differs in effects than intermittent exposure

Persistent PTH exposure: will favor bone reabsorption Intermittent exposure: bone formation

What is Forteo used for?

• Used for the treatment for postmenopausal women with osteoprosis at high risk of fracture

• Increase bone mass in men with primary or hypogonadal osteoporosis at high risk for fracture

• Men and women with glucocorticosteroid treatment at high risk for fracture

Describe how RANKL antagonists work in osteoporosis.

• RANKL is a receptor activator of nuclear factor kappa B ligand and plays a role in bone destruction

• A RANKL antagonist will inhibit osteoclast formation and stop bone destruction in pts with osteoporosis

What is the primary mediator of osteoclast formation, function and survival?

RANKL

What is the denosumab MOA?

RANKL Antagonist, leading the osteoclast to apoptosis

How is hyperparathyroidism treated?

The treatment for hyperparathyroidism would be to surgically remove the gland to make the patient go into hypoparathyroidism (similar with hyperthyroidism). Once the patient is in hypoparathyroidism, we would give the patient calcium, vitamin D, and PTH hormone replacement therapy if needed.

Primary hyperparathyroidism results in _______, and secondary hyperparathyroidism results in ________.

hypercalcemia, hypocalcemia