What are the normal serum calcium levels?
Normal serum calcium levels are 2.2-2.6mmol/L
How is calcium transported in the blood?
- Free ionized Ca2+
- Bound to plasma proteins
- Complexed with citrate
Where is most of the calcium in the body stored?
Skeleton – 99% is sequested bone in the form of hydroxyapatite crystals
What are the two primary functions of the skeleton?
- Structural support
- Maintains serum [Ca2+] (bone resorption & deposition)
Regulation of serum calcium is critically important for the execution of its various functions.
Identify some of these functions
- Regulates heart rhythm
- Mediates nerve transmission at NMJ
- Role in intracellular signalling pathways
- Assists in normal blood clotting
Which three substances are involved in the regulation of calcium levels?
- Parathyroid Hormone
- Vitamin D
Explain the role of PTH in regulating serum calcium levels
- Stimulates bone resorption and release of Ca2+ into circulation
- Stimulates Ca2+ reabsorption in kidney and excretion of phosphate
- Stimulates hydroxylation of 25-hydroxyvitamin D3 to make active Vitamin D (calcitriol)
Explain the role of dietary vitamin D in regulating serum calcium levels
- Increases intestinal absorption of dietary Ca2+ and renal reabsorption of Ca2+
- Increases bone resorption
Explain the role of calcitonin from the thyroid gland in regulating serum calcium levels
Calcitonin counteracts the effects of PTH
In terms of the feedback regulation of serum calcium, outline the body's response to increases in calcium levels
In terms of the feedback regulation of serum calcium, outline the body's response to decreases in calcium levels
Where are the parathyroid glands found?
What are the two kinds of cells found in the parathyroid glands?
Explain how calcium regulates the synthesis of PTH
Synthesis is regulated both at transcriptional and post transcriptional levels:
- Low serum calcium up-regulates gene transcription (prolongs survival of mRNA)
- High serum calcium down-regulates gene transcription
Describe the storage and synthesis of PTH
- PTH is continually synthesised but little is stored
- Chief cells degrade hormone as well as synthesis it
Identify the target organs of PTH and the different physiological effects brought about
- Bone – increase resorption
- Gut – activates Vitamin D and hence increases transcellular Ca2+ uptake from GI tract
- Kidney – decreases Ca2+ loss to urine
Where are calcium phosphate crystals found?
Calcium phosphate crystals found within collagen fibrils aka. hydroxyapatite crystals
Bone is dynamic.
Describe the processes of bone resorption and bone deposition
- Bone deposition: osteoblasts produce collagen matrix which is mineralised by hydroxyapatite
- Bone resorption: osteoclasts produce acid, dissolving the micro-environment hydroxyapatite
In 1-2 hrs PTH stimulates osteolysis.
In 4 steps, describe the action of parathyroid hormone on bone
⇒ PTH induces osteoblastic cells to synthesise and secrete cytokines
⇒ Cytokines stimulate differentiation and activity in osteoclasts and protect them from apoptosis
⇒ PTH decreases osteoblasts' activity exposing bony surface to osteoclasts
⇒ Reabsorption of mineralized bone releases of Pi and Ca2+ into extracellular fluid
Describe the effect of PTH on the tubular cells in the kidney in terms of calcium and phosphate reabsorption
A – PTH increases Ca2+ reabsorption in ascending limb and DCT
B – Pi is removed from circulation by inhibiting its reabsorption in the ascending limb and DCT (prevents calcium stone formation)
Dietary intake of calcium is typically 1000 mg/d.
Describe how this is usually absorbed?
- Only 30% is absorbed by a paracellular uptake
- Absorption is significantly increased by Vitamin D via transcellular uptake
How can we obtain Vitamin D?
Vitamin D is a lipid soluble vitamin that can be derived from plants or through action of sunlight on cholesterol in the skin
Identify and describe the two forms of Vitamin D
- D3 (cholecalciferol) made in skin and from dairy using sunlight
- D2 (ergocalciferol) made when yeast and fungi are added to margarines as a supplement
Identify two shared characteristics of the two forms of Vitamin D
- Both form calcitriol (active form of Vitamin D)
- Both are equipotent
Describe how active Vitamin D takes two hydroxylation reactions to turn cholecalciferol from skin or diet into calcitriol
- In the liver (C-25): 25-hydroxyvitamin D (major circulating hormone)
- In the kidney (C-1): 1,25(OH)2 / calcitriol
How is Vitamin D3 transported?
In the circulation vitamin D3 is bound to transcalciferin with only a small fraction in free form
Describe the hydroxylation of Vitamin D3 in the kidney
- Pre-vitamin is bound to carrier small enough to be filtered by the glomerulus and enter PCT
- Conversion to active form occurs by enzyme 1α-hydroxylase
What is the t1/2 of the active form of Vitamin D?
Explain the control of Vitamin D3 hydroxylation
- Elevated serum calcium prevents C-1 hydroxylation
- Elevated PTH stimulates C-1 hydroxylation to form calcitriol
What is the effect of calcitriol?
Calcitriol decreases the urinary loss of calcium by stimulating reabsorption in the kidney