Laboratory Investigation of Disorders of Calcium and Phosphate Metabolism Flashcards Preview

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Flashcards in Laboratory Investigation of Disorders of Calcium and Phosphate Metabolism Deck (32)
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1

Recap the stages of bone remodelling

  • ACTIVATION 
    • Stimulation of osteoclast differentiation (osteoclast progenitor to osteoclast) by detecting minor stress fractures 
  • REABSORPTION 
    • Osteoclasts will dissolve old bone, digesting the collagen matrix and release minerals into ECF
  • REVERSAL 
    • Signals to terminate osteoclast activity (osteoclast activity) and promote further osteoblast differentiation 
  • FORMATION 
    • Osteoblasts lay new bone (initially osteoid) 
    • Osteoid subsequently undergoes mineralisation to form new bone 

2

What induces osteoclast differentiation? 

RANK ligand binding to RANK receptor on pre-osteclasts activating transcription factor promoting differentiation of pre-osteoclasts into osteoclasts 

3

What competes with the RANK receptor for the RANK ligand? 

OPG (osteoprotogerin), a decoy receptor produced by osteocytes which prevents RANK-ligand from binding to RANK receptor, and inhibiting osteoclast differentiation to prevent excessive bone reabsorption 

4

What is denosumab? 

  • Monoclonal antibody 
  • Prevents RANK receptor activation and inhibiting osteoclast differentiation/ activity 
    • Therefore prevents the reabsorption phase and excessive bone loss 

5

What is denosumab used for? 

Treatment of osteoporosis 

6

What pathway induces osteblast differentiation? 

 

Wnt pathway 

7

How will osteoblasts be differentiated? 

  • Via the Wnt signalling pathway 
    1. Wnt signalling protein molecule which will activate the Wnt receptor (frizzled) in presence of co-factor LRP5 
    2. ß-catenin protein in the cytosol is released following Wnt binding and frizzled activation allowing it to act as a TF and promote specific differentiation pathways (osteoblast differentiation) 

8

What is the negative regulation of the Wnt signalling pathway? 

DKK (dickkopf) and sclerostin (SOST) proteins bind LRP5 co-receptor and prevent full activation of Wnt signalling pathway preventing osteoblast differentiation 

9

Why is bone turnover important? 

For homeostasis of calcium and phosphate 

10

What hormones affect the homeostasis of serum calcium and phosphate? 

  • PTH 
  • Vitamin D (1,25 dihydroxy D3) 
  • Calcitonin 
  • FGF-23

11

What are the actions of PTH? 

  • Promote Ca release from bone 
  • Increase renal Ca reabsorption via action on DCT 
  • Increase renal Pi excretion from DCT 
  • Upregulates 1 alpha hydroxylase activity 

12

What is the effect on PTH on bone? 

PTH receptors on osteoblasts and osteoclasts, increase bone remodelling 

  • Increase bone formation via osteoblasts 
  • Increased bone reabsorption after activating osteoclasts via RANKL 

13

What does the effect of PTH on bone depend on? 

Concentration Dynamics 

  • Intermittent low doses are anabolic (bone formation) 
  • Persistent high concentration leads to excess reabsorption over formation, causing bone loss due to increased calcium release causing bone de-mineralisation and loss 

14

What is Vitamin D? 

Calcitriol 

  • Steroid hormone (not vitamin) synthesised in the skin in response to UV exposure 

15

What are the actions of vitamin D (calcitriol)? 

  • Increase reabsorption of calcium and phosphate from GI tract 
  • Inhibit PTH secretion (by inhibiting transcription in chief cells in PTH gland) 
  • Complex effects on bone, generally in synergy with PTH 

16

How is Vitamin D activated and converted to the active hormone calcitriol? 

  1. 25 Hydroxylation of Vitamin D3 in liver to form 25OH D3, major circulating metabolite 
  2. 1 alpha hydroxylase will convert 25(OH)D3 to 1,25(OH)2D3 or calcitriol, the active hormone will bind nuclear receptor and affect transcription 

17

Where is 1 alpha hydroxylase located and what affects its activity? 

Located in the kidney 

  • Activity is increased by 
    • PTH 
    • Low phosphate 

18

What is the relationship betwen PTH and vitamin D 

PTH will activate vitamin D which will in turn via negative feedback limit the secretion of PTH via transcriptional control 

19

What is osteomalacia? 

The loss of bone mineral component/ failure of mineralisation of the osteoid = soft bones 

20

What is the most common cause of osteomalacia? 

Vitamin D deficiency 

  • Usually due to a combination of low dietary intake and lack of exposure to sunlight 

21

Who is at risk of Vitamin D deficiency? 

Elderly = if in nursing home and not taking supplements 

Breast fed babies kept out of sunlight 

22

What is vitamin D dependant rickets type I? 

Mutation in the 1 alpha hydroxylase enzyme 

 

23

What would the hormonal levels look like with someone with vitamin D-dependant rickets type I? 

24

What is vitamin D dependant rickets type II? 

Mutation in the vitamin D receptor 

  • Precursor levels are normal 
  • Calcitriol levels will be high, however not effective because it is not adequately activating its receptor 
  • Calcium and phosphate will be low 
  • PTH will be high 

25

What is hypophosphataemic rickets? 

Rare phosphate wasting condition (excessive phosphate excretion) condition leading to bone mineralisation defects 

26

What is the cause of hypophosphataemic rickets? 

  • Mutation leading to excess FGF-23 activity 
  • Ectopic FGF secretion (benign tumour) 

27

What is FGF-23? 

Hormone promoting renal phosphate excretion by reducing Na-Pi absorption from PCT 

28

What is FGF-23 synthesised by? 

FGF is a hormone synthesised and secreted by osteocytes 

29

What is the structure of FGF-23? 

FGF has a short half life and this half life fragment is regulated by enzymatic cleavage of the peptide into two inactive fragments 

30

How does FGF-23 cause hypophosphataemic rickets? 

  • Cleavage recognition site in hypophosphataemic rickets has a single amino acid substitution (mutation) that makes it unrecognisable and the peptide isnt cleaved remaining active and promoting excessive phosphate loss 
  • This leads to impaired bone mineralisation and rickets 

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