Control of Calcium and Phosphate Metabolism

Question 1

Calcium:
What are its functions?

Where is it stored?

How is it stored extracellularly?

What is the freely ionised Ca controlled by?

Answer 1

- • Bone growth and remodelling
• Cellular secretion, muscle contraction
• 2nd messenger, stimulus response coupling
• Blood clotting and co-enzyme functions
• Stabilisation of membrane potentials

• 99% in SKELETON, 0.99% extracellular, 0.01% intracellular
• 50% freely ionised, 50% bound to plasma proteins (Albumin)
• PTH and Vitamin D

Question 2

Phosphate:
What are its functions?

Where is it stored?

How is it stored extracellularly?

What is the free phosphate controlled by?

Answer 2

• • An element in high energy compounds (ATP), and secondary messengers (cAMP)
  • Phosphorylation/dephosphorylation of enzymes (activation/deactivation)
  • Constituent of DNA, Phospholipids, Bone
• 90% in SKELETON, 9.97% intracellular, 0.03% extracellular
• 50% free, 50% bound to plasma proteins
• Kidneys and the effects of PTH and FGF23

Question 3

What are the 2 types of bone?

What are the cells present in bone? Function?

Which stem cells differentiate into Osteoblasts and Osteoclasts? How?

Answer 3

• Cortical bone, and central Trabecular bone
• • Osteoblasts - formation
  • Osteoclasts - resorption
  • Osteocytes - trapped osteoblasts
• • MESENCHYMAL stem cells → osteoblast stromal cell → Osteoblasts
  • HAEMOPOIETIC stem cells → osteoblast stromal cell → Osteoclasts

Question 4

Osteoclast differentiation:
How do osteoclasts differentiate?

What does RANK stand for?

What inhibits osteoclast differentiation? How?

Answer 4

• Osteoblasts produce RANK ligands on their surface, which bind and activate the RANK receptor on osteoclast precursor cells = stimulates gene transcription and osteoclast differentiation
• Receptor Activator of Nuclear kappa beta
• Osteoprotogerin (OPG), which binds to RANK

Question 5

Which hormones activate and inhibit Osteoblasts?

Which hormones activate and inhibit Osteoclasts?

Answer 5

• • Activated by Oestrogen, Androgens, GH/IGF1, PTH, Vitamin D
  • Inhibited by Glucocorticoids
• • Activated by Thyroxine, Vitamin A, PTH
  • Inhibited by Oestrogen and Calcitonin

Question 6

Endocrine functions of bone:
What do the Osteocytes produce?
→ Where does it act and its effect?

What do the Osteoblasts produce?
→ Where does it act and its effect?

Answer 6

• Fibroblast Growth Factor 23 (FGF23)
  → KIDNEYS; decrease synthesis of vitamin D, increase excretion of phosphate

- Uncarboxylated Osteocalcin (uOCN)
→ • Pancreatic β-cells (↑Insulin)
• Adipocytes (↑Adiponectin)
• Muscle (↑Insulin sensitivity + glucose uptake)
• Stimulates Testosterone

Question 7

Parathyroid gland:
How many are there?

What cells does it consist of?

Blood supply?

What do they derive from?

Answer 7

• 4 (2 superior, 2 inferior) on the back of the thyroid
• CHIEF and OXYPHIL cells
• INFERIOR THYROID arteries
• Pharyngeal pouches III/IV

Question 8

Parathyroid hormone (PTH):
How does Ca affect the length of circulating PTH?

Functions of PTH?

What does Parathyroid Hormone Related Peptide (PTHrP) do? How does it relate to tumours?

Answer 8

• ↑Ca2+ = ↑Ratio of fragments to full length PTH
• • Stimulates Osteoblasts to produce M-CSF and RANK ligand = ↑Bone resorption
  • ↑Ca2+ reabsorption in DCT; inserts epithelial Ca channels (ECaC), stimulates Na/Ca Exchanger and ATPase
  • ↑Phosphate excretion
  • ↑1α-hydroxylase in PCT; conversion of active vitamin D
• Binds to specific PTH receptors; produced by tumours to cause hypercalcaemia

Question 9

What is Corrected Calcium?

Calcium Sensing Receptor (CaSR):
What pathways does an ↑Ca2+ cause?

What’s the overall effect of both pathways?

Answer 9

• Body works to have bound and free calcium in equilibrium; ↓Bound Ca2+ allows for H+ to take up the empty spaces on those plasma proteins = ↑Ionised [Ca2+] = Acidosis - opposite occurs to cause Alkalosis
• • Inhibition of AC = ↓cAMP/PKA
  • Activation of PLC = ↑IP3/DAG = ↑Intracellular Ca2+/PKC
• ↓PTH secretion

Question 10

Vitamin D:
What are the 3 stages of its formation? Where does each stage occur?

What does it bind to? What’s the effect?

What’s the effect of Vitamin D on Ca2+ absorption? How?

What’s the effect on PTH secretion and 1α hydroxylase?

What’s the effect on bone?

What other effects does it have on the body?

Answer 10

• 1. 7-Dehydrocholesterol → D3; Skin
     
     2. D3 →; Liver
     3. 25(OH)D3 → 1,25(OH)2D3; Kidney
• Binds to Nuclear receptor; stimulates DNA transcription
• ↑Ca2+ absorption in gut
  o Paracellular - through tight junctions
  o Transcellular - transporters move Ca into cell, which then binds to Calbindin and then moves out the other side
• ↓PTH secretion, ↓1α hydroxylase in kidney
• ↑Bone mineralisation = ↑[Ca2+]
• ↑Muscle strength, Cancer prevention, ↓Insulin resistance, CVD prevention

Question 11

Where are FGF23 receptors present?

How do the levels of Phosphate and Vitamin D3 affect FGF23 secretion?

What are the effects of FGF23 secretion?

Answer 11

• DCT, Choroid plexus (brain), Parathyroid glands
• ↑Phosphate and Vitamin D3 stimulates FGF23 secretion
• • Binds to kidney = ↑Phosphate excretion
  • Inhibits 1α hydroxylase = ↓Vitamin D3 = ↓Ca and Phosphate absorption in gut
  • ↓PTH secretion