Calcium homeostasis Flashcards
What is intracellular Ca2+ concentration?
0.1 micromolar
What is extracellular Ca2+ concentration?
2.4 mmol
What demands are stronger, plasma calcium or bone calcium?
Demands of plasma calcium are stronger, and the bones contains huge reserves of calcium that can be drawn on for some time before there is any appreciable weakening of the bones.
What is hypocalcaemia?
(Total Ca2+ < 1.2-1.5 mM) is very dangerous.
It increases neuronal membrane excitability by increasing sodium permeability causing tetany which is involuntary nerve-induced spasm of skeletal muscles.
Heart QT is also increased and heart failure may occur.
What is hypercalcaemia?
Only dangerous in the long term.
Decreases neuron excitability; calcium salts are rather insoluble so urinary stones and tissue calcification occurs.
Attempts to secrete excess calcium via urine causes polyuria, which leads to dehydration and exacerbates the problem.
How is calcium stored in bone?
99% is hydroxyapatite in a rather stable pool, 1% (250 mmol) is readily exchangeable.
How is phosphorous stored in the body?
85% in the skeleton as hydroxyapatite, 15% in soft tissues.
How is calcium gained and lost in the gut?
Gained through diet, lost through faeces
Is Ca2+ freely filtered in the kidney?
Ionised and complexed Ca2+ is freely filtered; protein-bound is not filtered.
Loss in urine
How does Ca2+ vary in foetus, pregnancy, puberty and old age?
Fetal plasma Ca2+ is slightly higher
Children, pregnant, lactating women: net accumulation of Ca2+ (3 mmoles/l)
Puberty: net accumulation of roughly (5 mmoles/l)
○ Postmenopause/ageing: Ca2+ loss and osteoporosis.
Is parathyroid hormone essential for life?
Yes
When and where is PTH released
PTH, a peptide hormone, is secreted from the parathyroid glands in response to falling plasma Ca2+ sensed by calcium receptors (G protein coupled).
PTH effects
PTH restores low plasma Ca2+ to normal and causes increased phosphate loss.
PTH effect on the kidney
Inhibits Na-phosphate cotransport and phosphate reabsorption in the kidney; phosphate loss causes an increase in Ca2+ mobilisation.
Increases Ca2+ reabsorption in the distal kidney tubule and collecting duct (independent of Na+ )
Increases activity of 1 alpha-hydroxylase and production of 1,25-OHD3
PTH effect on bone
Rapid effects: stimulates Ca2+ flux from bone across bone-lining cells; reorganises osteoblasts to allow (a) calcium efflux from matrix; (b) access of osteoclasts.
Long term osteoclast activation. Excess PTH limits growth of osteoblasts and bone matrix synthesis, causes destruction of bone.
PTH insufficiency
Hypoparathyroidism – low plasma Ca2+, tetany; pseudohypoparathyroidism – resistance to PTH due to receptor defect.
PTH excess
Hyperparathyroidism (tumours) – raised plasma Ca2+, bone destruction, urinary stones, sluggish CNS.
Vitamin D is
Calcitriol – 1,25(OH)2D3
What does vit D do to Ca2+?
Increases body calcium
Vit D synthesis
Synthesised in skin from cholesterol.
UV light converts a cholesterol derivative to cholecalciferol = Vitamin D3.
In the liver 25-hydroxylase -> 25-OHD3 (a long-lived inactive precursor store).
In kidney 1-alpha-hydroxylase -> 1,25(OH)2D3.
What receptors does vit 1,25-D3 act on?
Nuclear receptors
D3 on intestine
Increases uptake of Ca2+ via synthesis of the calcium binding protein, calbindin.
D3 in kidney
Facilitates conservation of calcium and phosphate for growth and repair.
D3 in bone
Necessary for the action of PTH; inhibits synthesis of collagen by osteoblasts; action on osteoclasts to increase bone breakdown and increase Ca2+ loss.
Deficiency of D3
Children - rickets. Renal rickets. Vit D-resistant rickets; Adults- osteomalacia.
Calcitonin function
Principal function – to prevent hypercalcaemia and excessive bone breakdown.
Where is calcitonin released from?
C cells of thyroid ( in response to high serum calcium)
Calcitonin effects
Surface cAMP-linked receptors.
Prevents hypercalcaemia by effects on bone.
Causes acute reduction in plasma phosphate, uptake to bone.
Bone calcitonin effects
Decreases activity of osteoclasts; inhibits mineral/matrix resorption; greatest effect when bone resorption is rapid (e.g. in the young).
Gut calcitonin effects
Meal related: helps to control rise in plasma Ca2+ due to absorption, also inhibits absorption.
Pregnancy/lactation related: protection against demands of fetus/infant.
Kidney calcitonin effects
Only pharmacological doses effect ion fluxes
Calcitonin deficiency
Deficiency – compensation by changes in PTH.
Excess calcitonin
Excess – uncontrolled secretion from ‘medullary’ carcinoma of thyroid. (NB in both these situations, serum calcium is maintained at approximately normal levels).
What 4 hormones regulate Ca2+ and PO4 3- homeostasis?
Parathyroid hormone (PTH), active vitamin D3 (1,25-dihydroxyVitD3), calcitonin and Fibroblast Growth Factor 23 (FGF23).
Difference between PTH and vit D3 roles?
VitD3 - promote mineralization of new bone -increase the absorption of both Ca2+ and PO4 3-.
PTH acts as guardian against hypocalcaemia - promotes the loss of PO4 3- (in addition to the increased absorption of Ca2+) in order to increase free plasma [Ca2+ ].
2 direct effects of PTH
PTH binds GPCR on PCT of kidney, and initiates the transcription of CYP27B1.
CYP27B1 converts inactive 25-hydroxyVitD3 (formed in the liver by CYP2R1) to active vitamin D3, 1,25 dihydroxyVitD3.
Same GPCR also decreases PO4 3- reabsorption/enhances PO4 3- secretion by altering the redistribution of Na/PO co-transporters away from the apical membrane (site of PO4 3- reabsorption).
How does vit D3 regulate its synthesis?
Active VitD3 down regulates it’s own synthesis by transcriptional inhibition of both CYP27B1 and PTH expression.
2 indirect PTH effects
PTH mobilize Ca2+ from bone by binding to it’s receptor on osteoblasts, which in turn activate osteoclasts through the RANKL signalling cascade.
Active VitD3 - enhances Ca2+ absorption in both DCT and intestinal mucosa through the Vitamin D Receptor (VDR, a nuclear receptor) dependent transcriptional upregulation of Ca2+-channels
How is PTH and D3 expression directly modulated by bone?
Osteocytes initiate the transcription of Fibroblast Growth Factor 23 (FGF23) in response to increased PO4 3- levels
FGF23 inhibits the transcriptional activation of both PTH in the parathyroid gland and CYP27B1 (and therefore active VitD3 formation) in the kidney
How does FGF23 affect PO43-?
Inhibit vitD3 activation
Decrease the VitD3 dependent absorption of phosphate in the gut.
Also decreases PO4 3- reabsorption/enhances PO4 3- secretion in the renal proximal convoluted tubules by altering the redistribution of Na/PO co-transporters away from their site of absorption in the apical membrane, similar to the effect of PTH.
What cells are involved in bone remodelling?
Osteoblasts (build bone), osteoclasts (absorb bone) and osteocytes (regulate and coordinate bone homeostasis).
Osteoclast vs Osteoblast origin
Osteoclasts are formed from hemopoietic precursors while osteoblasts come from mesenchymal precursors.
Bone remodelling cycle
Bone lining cells detach from bone at the site in need of remodelling and form the canopy of the Bone Remodelling Compartment (BRC), which allows osteoblasts precursors to invade the site.
Osteoblasts induce differentiation of osteoclast through the well-studied OPG (osteoprotegerin) /RANKL (nuclear factor-κB ligand) signalling cascade.
In addition, osteoclasts control osteoblast differentiation via Sema4D, in a negative feedback loop to ensure the bone building matches absorption.
Bone resorption by osteoclasts and bone deposition by osteoblasts is further coupled by TFG-B1 and IGF-1 released from the bone matrix by osteoclastic activity.
Osteocalcin links what
Bone homeostasis linked to energy metabolism
How does insulin affect bone?
Insulin binds to its’ receptor (InsR) on osteoblasts, repress OPG expression and activate osteoclastic activity through RANKL signalling.
How is osteocalcin activated
Inactive carboxylated osteocalcin trapped in the bone matrix is converted to active, decarboxylated osteocalcin in the acidic resorption lacunae of osteoclasts.
Where does osteocalcin bind?
Receptor on pancreatic β-cells, Osteocalcin stimulates insulin release
What proportion of plasma calcium is normally ionised?
50%
What is the concentration (with units) of free ionised calcium in the plasma?
1.2mM (half extracellular value)
How do glucocorticoids affect bone Ca2+
Increased reabsorption
Give two possible causes of rickets
Deficiency of vitamin D3 - inadequate exposure to sunlight/Food
X-linked hypophosphatemic rickets
The site of action of oestrogen to combat osteoporosis
Bone
A protein hormone secreted in response to decreased plasma calcium concentration
PTH
A hormone that can lead in excess to osteoporosis
Cortisol
A hormone that directly stimulates uptake of calcium from the gut
1,25 dihydroxyvitamin D3
A polypeptide hormone secreted in response to an increase in plasma calcium concentration
Calcitonin
A hormone that affects renal hydroxylation of vitamin D3
PTH
PTH directly affects
Kidney and bone
Calcitonin targets…
Bone, GI tract and kidney
