Lecture 1 - Endocrine Control of Calcium Homeostatis

Question 1

What is Jansen’s Metaphyseal Chondrodysplasia?

Answer 1

-Rare autosomal dominant disorder which results in short-limbed dwarfism -It is a PTH1R activating mutation which causes increased cAMP levels

Question 2

What is Blomstrand’s Chondrodysplasia?

Answer 2

-Rare Autosomal Recessive disorder which results in early lethality and advanced bone maturation -PTH1R inactivating mutations/deletions which DECREASE PTH induced cAMP formation

Question 3

Describe PTH2R.

Answer 3

-51% identical to PTH1R -Respond fully to PTH but binds PTHrP very poorly and is not stimulated by it -Its physiological role is less well understood

Question 4

Name Type 1 CaR agonists

Answer 4

-Divalent cations such as Ca2+ and Mg2+ -Spermine -Gd3+ -Aminoglycosides (neomycin)

Question 5

Name Type 2 CaR agonists

Answer 5

Type 2 CaR agonists are allosteric activators and include: -Calcimimetics (Cinacalcets) -Aromatic Amino Acids e.g. L-Phe

Question 6

Name CaR antagonists

Answer 6

-Calcilytics

Question 7

What are calcimimetics?

Answer 7

-Calcimimetics are positive allosteric modulators of the calcium receptor used for the treatment of primary and secondary hyperparathyroidism -Calcimimetics act by DECREASING PTH secretion

Question 8

What are calcilytics?

Answer 8

-Calcilytics are negative allosteric modulators of the calcium receptor which INCREASE PTH secretion. -Calcilytics have been proposed as an anabolic treatment for osteoporosis

Question 9

What is Calciphylaxis?

Answer 9

Calciphylaxis is a condition characterised by the necrosis of the skin and fatty tissue.

Question 10

What could be used to lower serum PTH levels in ESRD?

Answer 10

Cinacalcet could be used to lower serum PTH in ESRD

Question 11

Describe the effects of calcimimetics in comparison to VitD on PTH secretion.

Answer 11

Question 12

Why does hospitals use calcitriol rather than cincalet to treat hyperparathroidism?

Answer 12

Calcitriol is cheaper than Cinacalcet costing $37.50 as opposed to $486 a month.

Question 13

What novel anabolic therapy is in development for the treatment of osteoporosis?

Answer 13

A calcilytic compound, NPS 2143, is in the early clinical development for the treatment of osteoporosis.

Question 14

How does NPS 2143 act?

Answer 14

NPS 2143 acts by elevating PTH secretion through antagonising CaR activation.

Question 15

What are the two mechanisms by which Vitamin D receptors mediate the effects of 1,25(OH)₂D_3?

Answer 15

1) Activation of nuclear vitamin D receptor (nVDR) and transcriptional regulation of many vitamin D responsive genes.
2) Activation of nongenomic signal transduction pathways, most likely a membrane vitamin D receptor (mVDR)

Question 16

What abnormalities are seen in VDR knock-out mice?

Answer 16

VDR knock-out mice display no abnormalities prior to weaning but after weaning exhibit:

• Impaired growth formation (=vitamin D-dependent rickets type II)
• Uterine hypoplasia
• Growth retardation
• Alopoecia
• Hypocalcaemia
• Infertility