3. The parathyroid gland and calcium homeostasis

Question 1

Where are the parathyroids found?

Answer 1

Ar 4 poles of thyroid

Question 2

ParaT made up of which cells?

Answer 2

Chief cells: Parathyroid hormone secretion

Oxyphilic cells: Of unknown function

Question 3

Primary action of parathyroids?

Answer 3

Maintains plasma [ca2+]

Question 4

Effect of the following on plasma [ca2+]:

• Parathyroid hormone + vit D3
• Calcitonin

Answer 4

Parathyroid hormone + vit D3
—> Increase in plasma Ca2+ conc

Calcitonin
—> Decrease in plasma Ca2+ conc

Question 5

Where are the bodies calcium stores found?

Answer 5

99% in bone/teeth

Remaining 1% intracellular

Question 6

Of the 0.1% Ca2+ in plasma…

i.e. 2.3-2.6mM

Answer 6

50% free
45% bound to protein
5% chelated do di-carboxylic acids e.g. citrate and lactate

Question 7

Physiological functions of Ca2+?

Answer 7

• Prosthetic group for many enzymes and structural proteins (+/-calmodulin)
• Structure of the plasma membrane (essential for structure of Na+ channel and permeability of plasma membrane to Na+)
• Excitation-contraction coupling in muscle
• Excitation-secretion coupling at axonal terminals and in endocrine and exocrine glands
• Blood coagulation
• Major intracellular second messenger

Question 8

Body calcium homeostasis?

At gut + ECF + bone + kidneys

Answer 8

At gut:

• Intake from diet
• Excretion in faeces

At ECF:

• Intake from diet + bone resorption + reabsorption from kidneys
• Loss in secretion into gut to become faeces + in bone formation + filtration at kidneys

At bone:

• Intake from formation from ECF Ca
• Loss by resorption into ECF

At kidneys:

• Intake from ECF filtration
• Loss by ECF reabsorption or in urine

Question 9

Difference between body phosphate and calcium homeostasis?

Answer 9

Phosphate is also passed between ECF and soft tissues
There is a small phosphate store in ECF and bone
More Phosphate lost via urine
More Ca lost via faeces
More Phosphate absorbed from gut

Question 10

PTH regulation

Answer 10

Chief cells have Ca2+ sensing receptors that bind to Ca2+
On binding to the metatrophic receptors there is activation of PLC- PIP2-DAG pathway.
-PIP2 activates IP3 which leads to Ca2+ release from SR.
-DAG activates PKC which influences PTH exocytosis from secretory granule

Both these processes INHIBIT PTH synthesis and release

So [Ca2+] increase inhibits PTH release

Question 11

What is the process of PTH formation?

Answer 11

1. Pre-proPTH structure of 115 residues. Made up of:
   - Signal sequence
   - Pro sequence
   - Biologically active sequence
   - C-terminal fragment sequence

2. Pro-PTH structure of 90 residues @ ER
Made up of:
-Pro sequence
-Biologically active sequence
-C-terminal fragment sequence

3. PTH ready for secretion of 84 residues @ vesciles secretions. Made up of:
   - Biologically active sequence
   - C-terminal fragment sequence

Question 12

Processing of Pro-calcitonin in the para-follicular ‘C’ cells within the thyroid or brain neurones

Answer 12

Pro-calcitonin is processing in two ways.

1. In the Thyroid C cells by proteolytic processing to produce:
   - N-terminal peptide
   - Calcitonin
   - CCP (Calcitonin C-terminal peptide)
2. In the brain cells by proteolytic processing to produce:
   - N-terminal peptide
   - CGRP (calcitonin gene-releated peptide)
   - C-terminal peptide

Question 13

CCP ?

CGRP?

Answer 13

CCP - calcitonin C-terminal peptide

CGRP - calcitonin gene- related peptide

Question 14

What structures/cells make up cortical and trabecular bone?

Answer 14

Cortical bone structure at the centre
Trabecular bone: Lined by osteoblasts and OB precursors

Calcified bone matrix towards centre where the Haversian canal are found.

Osteocytes: Osteoblasts encased by calcified bone. Still have canaliculi connections. Mechanism of Ca movement to outer bone cells, key in remodelling

Question 15

Bone formation and resorption, action of osteoblasts and osteoclasts

Answer 15

Trabecular bone has more remodelling vs cortical
On bone surface it is lined with osteoblasts, involved in porotein secretion (e.g. collagen forming bone portein) and osteo-calcin and asteo-nectin formation. Ca and phosphate also released and concentration from blood used for remodelling

Osteoclasts are larger and resorbing bone

Osteoclasts and blasts work together

PTH and VitD act on osteoblast cells, stimulate to release factors. Osteoblasts essentially release growth factors e.g. M-CSF which stimulates stem cells differentiation into osteoclast precursors. Vit D and M-CSF act together to produce mononuclear osteoclasts from the osteoclast precursors. Mononuclear osteoclasts fuse to form osteoclast (which are muclinuclear)

RANK ligand and IL-6 are cytokines that stimulate osteoclast activity, their release is stijmualtes by PTH and Vit D

Question 16

Bone resorption process by osteoclasts?

Answer 16

Once formed they synthesise integrins from plasma membrane which bind to vitronectin to seal of an area of bone under the cell. This sealing allows the cell to control environment. By..

• Has v-type protein pump to allow it to pump acid which demineralises bone.
• Lysosomal enzymes are released
• Release of TRAP

Bone is reabsorbed. This process of stimulated by RANK ligand and IL-6 released from osteoblasts. Calcitonin inhibits bone resorption.

Question 17

Forms of vit D

Answer 17

Vitamin D3:
Different isoforms
Vit D3 either from diet or synthesised from cholesterol bi-product in endogenous steroid synthesis.
Endogenous form called cholecalciferol
In liver this cholecalciferol undergoes 25 hydroxylation then….
In kidney Vit D is formed into it’s activate metabolite form due 1 hydroxylation process

Vit D3
Hydroxylated to become activate

Question 18

Intestinal absorption of Ca2+

Answer 18

DIrect action with PTH in bone

VItamin D action in intestine, for Ca and Phosphate absorption.
1,25 dehydroxy VIt D binds to receptor in nucleus and interacts with Retinoid X receptor. These receptors are TFs, so found upstreams of genes. Protein synthesis in cytosol to produce proteins which are involved in Ca uptake channels across apical surface. Stimulates calbindin synthesis which is key for Ca absorption into interstitial space

Question 19

Intestinal absorption of Phosphate

Answer 19

Apical surface has Sodium-phosphate co transporter whuich can take 2 Na’s for 1 HPO4. VItamin D encourages transcription of proteins involved in phosphate absorption in to the interstitial space. Also proteins involved in the Na-K-ATPase.

Question 20

Feedback loops controlled plasma [Ca2+]?

Answer 20

Vit D responisble for Ca and phosphate uptake

Plasma Ca levels stimulate PTH release at low level and negatively inhibit PTH release at high levels

PTH is released into circulation and it’s main actions are in the kidney and the bone. In PTH in the bone there is bone resorption stimulated by binding to osteoblast binding. Leading to growth factors (cytokines e.g. RANK and IL-6) release to stimulate osteoclasts, leading to bone re-sorption. Ca and phosphate plasma levels increase

PTH actions in kidney
Ca reabsorbed in PCT mainly (65%). PTH binds to epithelial receptors and increases Ca reabsorption.
It also suppresses Phos reabsorption. This is bc you don’t want high levels of both minerals otherwise precipitation of Ca-Phos occurs.
PTH stimulates activation of Vit D in the kidney

Active VIt D stimulates Ca and Phos absorption in intestine and reabsorption of both in kidney.

PTH > Vit D

Question 21

What stimulates calcium and phosphate reabsorption back into blood in kidney from tubule?

Answer 21

VITAMIN D

Same mechanisms as seen in the intestines

Question 22

What is the active form of Vit D?

Answer 22

1,25 hydroxy Vit D

Question 23

High plasma levels of Ca and phos drive….

Answer 23

Bone synthesis but Vit D is essential for their uptake remember.

Question 24

PTH action in kidney?

Answer 24

Ca reabsorbed in PCT mainly (65%). PTH binds to epithelial receptors and increases Ca reabsorption.
It also suppresses Phos reabsorption. This is bc you don’t want high levels of both minerals otherwise precipitation of Ca-Phos occurs.
PTH stimulates activation of Vit D in the kidney

Question 25

Difference in reabsorption and absorption effect of PTH and Vit D

Answer 25

Active VIt D stimulates Ca and Phos absorption in intestine and reabsorption of both in kidney.

PTH stimulates both in intestine but only Ca reabsorption in kidney