Disorders of Calcium and Phosphate Metabolism Flashcards
1.Explain how osteoblast differentiation is induced by the RANK ligand?
• RANK (receptor activator of nuclear factor kappa-B) surface receptor on pre-osteoclasts stimulates osteoclast differentiation when RANK-L binds to it.
o RANK-ligand: produced by pre-osteoblasts, osteoblasts and osteocytes.
• OPG (osteoprotogerin): decoy receptor produced by osteocytes that binds to RANK-L to prevent the activation of RANK and so inhibits osteoclast differentiation.
- What inhibits osteoclast differentiation?
OPG (osteoprotogerin): decoy receptor produced by osteocytes that binds to RANK-L to prevent the activation of RANK and so inhibits osteoclast differentiation.
- What is the WNT signalling pathway?
- A highly conserved, complex signal pathway that is involved in animal development - Drosophila wingless gene (1987)
- WNT binds to the frizzled receptor which requires the co-factor LRP5/6 to become activated. The activated receptor activates B-catenin which migrates to the nucleus to bind to transcription factors (e.g. TGF)- osteoblast differentiation
- What is the WNT negatively signalled by?
DKK (dickkopf) and sclerostin (SOST).
- What is osteoCLAST differentiation:
- Promoted by
- Inhibited by
- Promoted by RANK-L/M-CSF
- Inhibited by NO/OPG.
- What is osteoBLAST differentiation :
- Promoted by
- Inhibited by
- Promoted by NO/ATP/PGE2
- Inhibited by SOST/DKK1/SFRP1
- Calcium homeostasis has already been covered in another lecture so a quick overview
- What % of body calcium is in bone and intracellular
- What amount of extracellular plasma is there?
- How much is bound, how much is free?
- What maintains Ca balance
- 99% of body calcium is in bone and the remaining 1% is mainly intracellular
- Extracellular: plasma Ca 2.2-2.6 mmol L-1
- About half is free [Ca2+] (physiologically active), half protein bound (mainly albumin).
- Hormonal control of the tiny (<0.1%) extracellular fraction is what maintains Ca balance.
- Where is Ca absorbed from and how?
•Ca is absorbed from the gut using vitamin D which is produced by PTH (PTH causes Ca reabsorption from the kidneys/gut and release from the bone).
- What % of the bodies phosphorus is in the bone?
•85% of body phosphorus is in bone and remainder is mainly intracellular
- What form is extracellular phosphorus in?
H2PO4^-, HPO4^2-
- What amount of plasma Phosphate should there be? What is an appropriate reference range?
2.5 - 4.5 mg dL-1 (0.75-1.45 mmol L-1)
- Where is Pi absorbed from and how?
•Pi is absorbed from the gut via vitamin D which is produced by PTH (PTH causes Pi excretion from the kidneys).
- How is Pi regulated by FGF-23?
•Pi is also regulated by FGF-23 from osteoclast which promote Pi excretion and inhibits vitamin D activation.
- Case Study:
A 75 year old widow was investigated for bone pain and muscle weakness. She told the GP that she was vegetarian and rarely left her home.
Serum investigations: Total calcium 1.82 mmol/l (2.20 - 2.52) Phosphate 0.70 mmol/L (0.75 - 1.50) Albumin 39 g/L (35 - 48) Alkaline phosphatase 187 U/L (30 - 100) Creatinine 69 umol/L (60 - 110)
Interpret these results?
LOW calcium
LOW phosphate
HIGH alkaline Phosphatase
• Vitamin D deficiency (diet and sunlight) causes low Ca and Pi – increase PTH to try to increase vitamin D.
- What is another name for vitamin D?
Calcitriol
- Is vitamin D a vitamin or a steroid hormone?
Steroid Hormone
- How is Vit D synthesised and then activated?
• Synthesised in skin in response to exposure to UV (‘sunshine vitamin’) and activated by 2 metabolic steps
o 25 hydroxylation in liver to form 25OH D3, major circulating metabolite
o 1α hydroxylation of 25 OH D3 in kidney produces 1,25(OH)2 D3, or calcitriol, the active hormone
- What is the difference between type 1 and type 2 dependant rickets?
Type 1 :
-Lack of 1 alpha hydroxylase enzyme
Type 2 :
- Lack of Calcitriol receptors
- 1 alpha hydroxylase enzyme is present
- What levels (ie high or low) would you see of :
-Ca
-Pi
- 25 OH D3
- 1,25 (0H)2 D3
-PTH
Would you see in VIt D deficiency ?
- Ca = LOW
- Pi = LOW
- 25 OH D3 = LOW
- 1,25 (0H)2 D3 = NORMAL
- PTH = HIGH
How can calcitriol be normal in Vit D deficiency? Point is, it’s inappropriately normal – with low Ca and Pi it should be higher.
- What levels (ie high or low) would you see of :
-Ca
-Pi
- 25 OH D3
- 1,25 (0H)2 D3
-PTH
Would you see in Renal disease ?
- Ca = LOW
- Pi = HIGH
- 25 OH D3 = NORMAL
- 1,25 (0H)2 D3 = LOW
- PTH = VERY HIGH
- What levels (ie high or low) would you see of :
-Ca
-Pi
- 25 OH D3
- 1,25 (0H)2 D3
-PTH
Would you see in 1 alpha hydroxylase mutation ?
- Ca = LOW
- Pi = LOW
- 25 OH D3 = NORMAL
- 1,25 (0H)2 D3 = VERY HIGH
- PTH = HIGH
- What levels (ie high or low) would you see of :
-Ca
-Pi
- 25 OH D3
- 1,25 (0H)2 D3
-PTH
Would you see in Vit D receptor mutation ?
- Ca = LOW
- Pi = LOW
- 25 OH D3 = NORMAL
- 1,25 (0H)2 D3 = VERY HIGH
- PTH = HIGH
- How can a mutation result in hypophosphataemia ?
Mutation leading to excess FGF-23 activity
Ectopic FGF secretion (benign tumour)
24. What levels (ie high or low) of: Ca Pi 25 OH D3 1,25 (OH)2 D3 PTH FGF-23 would you expect to see in X-linked hypopho-phataemic rickets , Autosomal dominant hypopho-phataemic rickets and Oncogenic osteomalacia ?
Ca = Low / Normal Pi = Low 25 OH D3 = Normal 1,25 (OH)2 D3 = Low/Normal PTH = High/Normal FGF-23 = High
- Where is FGF-23 secreted from?
Osteocytes
- When was FGF-23 discovered
2000
- What is Hypophosphatemic rickets?
A rare phosphate-wasting conditions leading to bone mineralization defects (osteomalacia)
- What causes Hypophosphatemic rickets?
Consortium investigating autosomal-dominant HR (ADHR) traced mutation in gene that turned out to be FGF-23
- Which hormone plays a central role in phosphate homeostasis?
FGF-23
- Explain the structure of FGF-23 ?
glycoprotein with 251 amino acids
signal peptide of 24 amino acids in the N-terminal portion
Next to the signal peptide is the FGF homology region
And then the C terminus
Furin cleaves the active form into inactive
- What is the half life of FGF-23 normally and when there is a mutation?
o Normally: short half-life due to enzymatic cleavage (Furin).
o Recognition sequence mutation: enzyme can’t recognise the cleavage sites, so the peptide remains in circulation for longer causing excessive Pi excretion and excessive inhibition of Vit D production.
- Explain the actions and interactions of FGF-23?
- FGF-23 action: reduced PTH, reduced active vitamin D production and Pi excretion.
- FGF production is increased by PTH, increased Pi and increased vitamin D.
- PTH causes Pi excretion and vitamin D production.
- Vitamin D causes Pi reabsorption and PTH inhibition of PTH production.
- What is Renal Osteodystrophy
alteration of bone morphology–> Reduced renal function
- What causes Renal Osteodystrophy?
- Reduced production of activated vitamin D which causes hypocalcaemia (reduced reabsorption), this increases PTH production which causes bone erosion/resorption.
- Reduced H+ excretion causes metabolic acidosis which also causes bone erosion
- How does renal phosphate reabsorption work?
Sodium-phosphate co-transporter
Requires association with Na-H exchanger regulatory factor (NHERF)
