Lecture 16

Question 1

What does the parathyroid do?

Answer 1

It’s the main regulator of your extracellular calcium pool (important for maintaining calcium levels in your blood. It will increase calcium concentrations and decrease phosphate concentrations in the blood.

Question 2

The parathyroid works on which three main organs?

Answer 2

The parathyroid works on the bones, kidneys, and intestines.

Question 3

What would occur if you did not have parathyroid hormone or have an insufficiency or too much of your parathyroid hormone?

Answer 3

If you did not have parathyroid hormone or had issues with your parathyroid hormone, calcium levels are going to decrease dramatically over the course of just a few hours. An insufficiency of parathyroid hormone would lead to hypoparathyroidism, which can cause hypocalcemia and can lead to shaking.
Too much parathyroid hormone can lead to hyperparathyroidism, which can lead to kidney stones and weak bones.

Question 4

How many parathyroid glands do people typically have and where are they located? Which gender is more likely to get hyperparathyroidism?

Answer 4

People have 4 glands which adhere to the posterior surface of the thyroid gland. Females tend to get hyperparathyroidism more often since the masses of their parathyroid glands tends to be higher than males.

Question 5

Can you live without your parathyroid glands?

Answer 5

No but they can still function at half mass. We will have to get supplemented with parathyroid hormone

Question 6

What are the two main cell types of the parathyroid?

Answer 6

Chief Cells: produce majority of parathyroid hormone
Oxyphil cells: larger than chief cells with lots of mitochondria inside

Question 7

What kind of hormone is parathyroid hormone? Explain the process of how parathyroid hormone is “matured”. What happens when parathyroid hormone is formed?

Answer 7

Parathyroid hormone is a relatively small peptide hormone with no disulfides. Parathyroid hormone is expressed as a preprohormone that has its signal sequence cleaved twice to yield mature parathyroid hormone. When it’s formed, it’s packaged into secretory vesicles.

Question 8

How is the transcription and post-translation of parathyroid hormone regulated?

Answer 8

Parathyroid hormone transcription and post-translation is regulated through cAMP (acts as nuclear receptor CREBP to upregulate gene expression.
Vitamin D and high levels of intracellular calcium are going to down-regulate transcription of parathyroid hormone. The reason for this is because the whole point of parathyroid hormone is to increase intracellular calcium levels. If there is already high levels of intracellular calcium, we don’t need to produce any more PTH.

Question 9

What do low plasma concentrations of calcium and phosphate do to PTH mRNA?

Answer 9

Low plasma concentrations of calcium are going to lead to prolonged survival of the PTH mRNA transcript. This means that more PTH will be produced as a result. Low plasma concentrations of phosphate are going to accelerate PTH mRNA degradation. Since concentrations of calcium will be higher as a result of low phosphate concentrations is plasma, this will lead to that increased degradation of PTH mRNA.

Question 10

What do chief cells do when plasma concentrations of calcium are high?

Answer 10

Chief cells are able to degrade parathyroid hormone in response to high plasma calcium levels such that the levels are adjusted to the needs of the organism.

Question 11

What portion of mature parathyroid hormone is biologically active?

Answer 11

The entire biological activity of parathyroid hormone is localized with the first 34 amino acids.

Question 12

What does the parathyroid gland respond to?

Answer 12

Ionized calcium levels. Not calcium bound to things

Question 13

What stimulates the parathyroid gland to release parathyroid hormone? What inhibits the parathyroid gland from releasing parathyroid hormone?

Answer 13

Decreased calcium levels in serum are going to stimulate the parathyroid gland to release PTH. High levels of calcium in serum are going to inhibit the parathyroid gland from releasing PTH

Question 14

What is the entire purpose of parathyroid hormone? Where does parathyroid hormone act on in order to make this happen?

Answer 14

PTH1 receptor: present in bone and kidney
PTH2 receptor: in peripheral tissues that rely on calcium including the CNS, the pancreas, the testis, and in the placenta.

Question 15

How is the secretion of parathyroid hormone controlled?

Answer 15

By a negative feedback loop. There are calcium sensing receptors present on parathyroid cells which become activated when [Ca++] is too high.
This leads to activation of phospholipase C that then inhibits further PTH secretion from storage granules in parathyroid cells.

Question 16

What does parathyroid hormone do when it reaches target cells?

Answer 16

When you have low levels of calcium in your blood, parathyroid hormone will get released and will bind to PTH receptors (GPCRs)
Binding of parathyroid hormone to the PTH GPCRs which will lead to two pathways becoming activated: cAMP pathway, and the IP3/DAG pathway (integration of pathways). The PTH receptors are coupled to adenylyl cyclase through Gαs and to phospholipase C through Gαq.
As a result of both cAMP and IP3/DAG being formed (from activation of Gαs and Gαq), both PKA and PKC become activated.

Question 17

What is pseudohypoparathyroidism and how does it occur? What are the characteristics for individuals which have pseudohypoparathyroidism?

Answer 17

Since parathyroid hormone function relies so heavily on cAMP, people who have issues with cAMP can develop something that looks like hypoparathyroidism but is not hypoparathyroidism. Individuals which have pseudohypoparathyroidism do not have issues with parathyroid hormone, they have issues with the cascade following the binding of PTH. People are unresponsive to parathyroid hormone treatment. Half of reported cases of pseudohypoparathyroidism that are unresponsive to PTH are attributed to a genetic defect in the Gαs protein. Individuals which have pseudohypoparathyroidism tend to have short statures, be overweight, have a round face, have wider/stubbier fingers, their last two metacarpals (4 and 5) produce dimples instead of knuckles (dimple knuckles formation), and they tend to form specific mental disabilities.

Question 18

How is calcium increased when parathyroid hormone is secreted?

Answer 18

When parathyroid hormone is secreted, parathyroid hormone will end up activating osteoblasts in efforts to mobilize calcium (Ca++)- which is weird because osteoblasts BUILD bone? Oddly enough, parathyroid hormone receptors are only present on osteoblasts, and not on osteoclasts. PTH will inhibit further osteoblasts from being made. Essentially, osteoblasts bind PTH on using PTH receptor, causing GPCR cascade to initiate, thereby increasing cAMP. This inhibits collagen synthesis, inhibits calcium from being deposited into osteoid (unmineralized bone), and tells osteoclasts to begin secreting enzymes and phagocytize the bone to release Ca++.

Question 19

What does parathyroid hormone do to the kidneys such that Ca++ levels can be increased in the blood?

Answer 19

Parathyroid hormone is going to bind to the GPCRs and is going to lead to activation of both Gq such that phospholipase C is activated to form DAG and IP3 from PIP2 and Gs. Objective is to increase extracellular calcium (Ca++). This is then going to lead to an increase in urinary cAMP levels.The activation of these pathways then ends up leading to increased renal excretion of phosphate, and increased renal absorption of calcium. More steps occur before this, however we just need to know that cAMP increases as a result of the Gq and Gs pathways being activated, thus causing this increased excretion of phosphate and increased absorption of calcium to occur in the kidneys.
This will also stimulate the production of the active form of vitamin D (calcitriol). This is important because this will allow us to be able to absorb and utilize the calcium we have properly.

Question 20

What does calcium balance in the blood depend on entirely?How does both hyperparathyroidism and hypoparathyroidism affect the intestinal uptake of calcium?

Answer 20

Calcium balance is going to entirely depend on the intestinal absorption of dietary calcium - if you don’t take in calcium from intestines (from diet), you are going to have a calcium deficiency (which must then be supplemented from the bones).
Essentially, having hyperparathyroidism means that you will have more parathyroid hormone, meaning you will produce more calcitriol (which allows your intestines to be able to take up calcium as a result). If you have hypoparathyroid, you have less PTH (meaning you produce less calcitriol, which prevents you from being able to take up as much calcium from your intestines).

Question 21

What is PTHrP, what is it related to in funciton, and where is it secreted from?

Answer 21

PTHrP is called Parathyroid Hormone-Related Peptide which is secreted from tumors (HHM) - the reason that HHM (humoral hypercalcemia of malignancy) occurs is because of PTHrP’s similarity to PTH (thus causing increased mobilization of calcium when not needed). It was originally thought that parathyroid hormone was secreted from tumors as well because PTH and PTHrP have very similar effects in the body (both result in osteoclast activity, causing bone resorption and subsequent release of calcium into the blood steam). However it was determined that PTHrP was a different peptide than PTH.

Question 22

Where is the mRNA for parathyroid hormone related peptide (PTHrP) expressed? What are the possible functions of PTHrP?

Answer 22

The mRNA for PTHrP is expressed in the parathyroid glands (just at lower levels), lactating breast tissue, the pituitary, among others…

Possible functions of PTHrP are:
- Stimulates placental Ca2+ transfer
- Smooth muscle contraction as well as acting as a relaxant after birth
- Secreted in human milk
- Causes vascular smooth muscles to relax.
- Causes chondrocytes (cartilage cells) in developing bone to grow and differentiate.
PTHrP is not involved in normal calcium homeostasis (this is the role of PTH), meaning it is not found in blood plasma of normal individuals.

Question 23

What does calcitonin do, and where is it secreted from?

Answer 23

Calcitonin is a single chain polypeptide which inhibits osteoclast functions. Calcitonin will also lead to decreased reabsorption of calcium in the kidneys. This means that calcitonin does play a role in calcium levels in the blood. It’s secreted by the c-cells of mammalian thyroid glands and is secreted by the ultimobranchial bodies or amphibians and birds.

Question 24

What 2 proteins does the calcitonin gene support?

Answer 24

Calcitonin and calcitonin gene related peptide (CGRP)

Question 25

Does removing the thyroid gland (thyroidectomy) affect calcium homeostasis?

Answer 25

No, removal of the thyroid does not lead to any effect on calcium homeostasis. The reason for this is that the main regulatory for calcium homeostasis is parathyroid hormone.

Question 26

Why are other animals calcitonin (like salmon calcitonin) used clinically?

Answer 26

At high levels of calcitonin (human calcitonin) in humans, nothing really happens. However, other animals have calcitonin which has much more of an effect (other animals calcitonin also has longer half lives than human calcitonin). Because of this, other animals calcitonin (like salmon calcitonin) can be utilized to clinically treat hypercalcemia (hyperparathyroidism), elevated parathyroid hormone related peptide (PTHrP), as well as Pagets disease.

Question 27

What is Pagets disease characterized by and what causes it?

Answer 27

Characteristics of Pagets Disease is that in some regions of the body will have more osteoclast activity, and because of this (due to weakness), the body compensates to have more osteoblast bone repair in that area (thus creating areas of enlargement of the bone, but the bones are much weaker). This can lead to bone pain, an enlarged head, arthritis and osteoarthritis, a loss of hearing (affects specific bones in your ear), bowed arms and legs, etc. Individuals are also hypersensitive to things that activate osteoblasts and osteoclasts (vitamin D for example). Pagets disease can be caused through viruses, it can be caused by genetics, and air pollution is thought to play a role in the activation of this.

Question 28

What is the treatment for Pagets disease? What else can this treatment help treat?

Answer 28

The treatment for Pagets disease is bisphosphonates as well as calcitonin management. Bisphosphonates are a class of drugs which promote osteoclast apoptosis (programmed cell death). By breaking down osteoclasts, this prevents bone from being broken down. Bisphosphonates are used to treat osteoporosis as well (and are used in addition to treat Pagets disease). Because of this drug, the osteoclasts aren't excessively breaking down the bone, and the osteoblasts do not have to overcompensate and try and build bone quickly.

Question 29

What type of bone does osteoporosis affect mostly?

Answer 29

Osteoporosis affects trabecular (spongy) bone more than cortical bone.

Question 30

What is primary hyperparathyroidism, and what happens as a result of this disease?

Answer 30

Primary hyperparathyroidism means that you have issues with the release of parathyroid hormone (too much). This leads to hypercalcemia, prolonged bone reabsorption (weaker bones), and elevated vitamin D.

Question 31

What are rickets (osteomalacia), what are the symptoms of rickets, and what is the most common cause? Is this metabolic bone disease more common in adults or children?

Answer 31

Rickets are defective calcification of osteoid - leading to softer bones which bow (bend). Symptoms of rickets include diffuse body pains (pain more-or-less all over the body), muscle weakness, and fragility of bones. The most common cause of rickets is a deficiency in vitamin D, which can result from an issue with sunlight exposure (since sunlight is important for vitamin D). This metabolic bone disease is more common in children than it is adults.