Calcium homeostasis

Where is most calcium found?

Bone

Calcium gradient

More extracellularly than intracellularly

Importance of Ca2+ gradient

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* Lipid bilayer impermeable to calcium
* Ca2+ influx into cytoplasm is controlled by Ca2+ channels
* Allows Ca2+ to function as signalling ion to activate intracellular processes

Calcium is gained through…

* Diet


* Gut absorption

Calcium is lost through…

* Urine
* Regulated by kidneys

Calcium is exchanged through…

Bone

Hormones involved in calcium regulation

* Parathyroid hormone
* Calcitonin
* Active vitamin D

When is parathyroid hormone released?

Released in response to falling levels of circulating calcium

Parathyroid hormone secretion control

* PTH protein stored in secretory granules of chief cells
* Released from cells is regulated by concentration of circulating calcium
* High calcium inhibits secretion
* Low calcium allows secretion

Effects of parathyroid hormone on bone

Ca2+ salts immediately release from osteoblasts

Breakdown of hydroxyapatite crystals from osteoclasts

How does calcium get quickly released from bone

PTH binds to osteoblast

Activates pathways which express calcium pathways/exchangers

Calcium passes from bone, into osteoblast layer, into circulation

How does calcium get slowly released from bone?

Slow exchange – bone dissolution through osteoclast activity

PTH binds to osteoblast

Other mediators released (eg RANK ligand)

Rank ligand acts to cause maturation of osteoclasts

Increased bone resorption causes release of calcium

Effects of parathyroid hormone on kidney

* Increased kidney tubular reabsorption of Ca2+ into blood to prevent loss through urine
* Promotes active vitamin D formation

Effects of PTH on intestine

Enhanced absorption of calcium from intestine

What structures does PTH affect

* bone
* kidney
* intestine

When is vitamin D released

In response to falling levels of blood calcium

What regulates vitamin D production?

PTH

Production of active vitamin D from cholesterol

1. Cholesterol exposed to UV light in the skin producing cholecalciferol
2. Cholecalciferol converted to 25-hydroxycholecalciferol in liver
3. 25-hydroxycholecalciferol converted by renal 1a-hydroxylase in the kidney into active vitamin D (regulated by PTH)

Biological actions of active vitamin D

* Good for longer-term regulation of Ca2+ homeostasis
* Increases absorption of Ca2+ from intestine to prevent stripping calcium from bone
* Lipophilic so can move through membrane and affect transcription to allow movement of calcium through cell

When is calcitonin released

Secreted rapidly in response to elevated calcium (eg after meal)

What secretes calcitonin

C-cells

Biological actions of calcitonin

* Reduce blood Ca2+ levels
* Prevent hypercalcemia (high calcium)
* Primary target tissue: bone and kidney
* Inhibits bone resorption (decreases entry of Ca2+ from the skeleton into plasma)
* Reduces Ca2+ reabsorption in kidneys so more lost in urine

Disease caused by vitamin D deficiency

Causes rickets (children) and osteomalacia (adults)

Why does vitamin D deficiency occur?

* Diet lacking vitamin D
* Lack of sunlight
* Lack of renal 1a-hydroxylase (genetic disease)

Mechanism of rickets

* Low levels of active vitamin D
* Low levels of calcium uptake in gut
* Low calcium levels = increased levels of PTH
* Increased PTH = increased calcium resorbed from bone
* Calcium stripped from bone so cartilage not properly mineralised resulting in weak, malformed bones (bowed legs)

Hyperparathyroidism

Excessive PTH secretion by parathyroid glands

Primary hyperparathyroidism

Parathyroid cells secrete unregulated, excessive amounts of PTH (eg due to cancer of chief cells)

* Calcium resorption from bone = lower bone density, more bone fractures
* Calcium uptake in kidney

Secondary hyperparathyroidism

Occurs due to chronic renal failure which leads to excessive PTH secretion

Why does secondary hyperparathyroidism occur?

No kidney function

* Active vitamin D production
* Ca absorption in gut
* Ca retention in kidney
* hypocalcaemia
* PTH production

Hypoparathyroidism

Inadequate PTH secretion

Effects of Hypoparathyroidism

Decreased PTH

* Active vitamin D production = Ca absorption in gut
* Bone resorption
* Ca retention in kidney

Hypocalcaemia

* Increased neuromuscular excitability due to change in availability of cations

Enamel hypoplasia

* Incomplete/defective formation of organic enamel matrix of teeth in embryonic stage of the tooth
* Seen in children with chronic diseases of calcium homeostasis
* Vit D deficiency, hypoparathyroidism
* Low serum calcium during enamel formation
* Increased susceptibility to caries