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• Functions of Vitamin D3


  • Increase the active transport of Ca+2 and phosphate from the intestine
  • Increase the reabsorption of Ca+2 from PCT
  • Increase Osteoblast activity
  • Secondary increase in osteoclast activity

  
• Vitamin D3


  Also called cholecalciferol

  
• Vitamin D3 synthesis


  1. From 7-dehydrocholesterol in the skin by the action of sunlight (previtamin D3 is formed rapidly which then slowly converted to vitamin D3)

  2. Ingestion of diet

  
• Transport of Vitamin D3

  Vitamin D3 and its hydroxylated derivatives are transported in plasma bound to vitamin D-binding protein (globulin)

  
• Activation of Vitamin D3


  1. In the liver: by CYP450 converted into 25-dydroxycholecalciferol (25-OHD3)

  2. In the kidney: by the action of 1α-hydroxylase in PCT converted into 1,25-dihydroxycholecalciferol (1,25-(OH)2D3 "also called Calcitriol")

  3. 1,25-(OH)2D3 also made in the placenta, in keratinocytes in skin and in macrophages

  4. 24,25-(OH)2D3 also formed in the kidney but is less active

  
• Plasma level of 25-OHD3 = 30ng/mL
• Plasma level of 1,25-(OH)2D3 = 0.03ng/mL
• When plasma Ca+2 level is high (Hypercalcemia)


  • Little 1,25-(OH)2D3 is produced
  • The kidney produced 24,25-(OH)2D3 (relatively inactive) instead
  • Ca+2 absorption is reduced from intestine (Adaptation)

  
• When plasma Ca+2 is low (Hypocalcemia)


  • PTH secretion is increased
  • PTH stimulate an increase the expression of kidney 1a-hydroxylase
  • 1,25-(OH)2D3 production is increased
  • Ca+2 absorption is increased from intestine

  
• When plasma phosphate is low

  Production of 1,25-(OH)2D3 is increase
• When plasma phosphate is high

  Production of 1,25-(OH)2D3 is reduce
• When 1,25-(OH)2D3 formation increase


  • It exerts: -ve feedback on 1α-hydroxylase
  • -ve feedback on PTH secretion by parathyroid glands
  • +ve feedback on 24,25-(OH)2D3

  
• PTH


  Liner 84 amino acid (a.a.) Polypeptide
• PTH


  • Secreting cells: Chief cells of parathyroid glands
  • Source: 115 a.a. preproPTH
  • Modification: in EPR the leader sequence removed to form 90 a.a. ProPTH. THEN in Golgi apparatus the 6 a.a. are removed to for 84 a.a. PTH which THEN packaged in secretory granules

  
• Plasma level of PTH: 10-55pg/mL
• Half-life of PTH: 10min
• Metabolism of PTH


  Rapid in Kupffer cells of liver into inactive fragments

  
• Excretion of PTH


  in the kidney (PTH and its inactive fragments)
• Effects of PTH


  • Increase plasma Ca+2 and decrease plasma phosphate
  • Increase bone resorption (activation of osteoclasts)
  • Decrease phosphate reabsorption via effects on NaPi-Iia in PCT (phosphaturic effect)
  • Increase Ca+2 reabsorption from DCT
  • Increase formation of 1,25-(OH2)D3 thus increase intestinal absorption of Ca+2

  
• In hyperparathyroidism, Ca+2 mobilization >> Ca+2 reabsorption this cause Ca+2 excretion in urine

  
• Effects of PTH on Bone remodeling

  • On longer time, PTH stimulates both osteoblasts and osteoclasts

  
• When plasma Ca+2 is high

  • Inhibits PTH secretion
  • Ca+2 deposition in the bone (Store)

  
• When plasma Ca+2 is low


  • Stimulates PTH secretion
  • Increase Ca+2 mobilization from bone (bone resorption)

  
• Mechanism of Ca+2 regulation of PTH

  Calcium sensing receptors (CaSR) in chief cells activated by high plasma Ca+2 and causes inhibition of PTH secretion

  
• Role of 1,25-(OH)2D3


  • Directly inhibits preproPTH mRNA synthesis in chief cells
  • 1,25(OH)2D3 formation is inhibited by high plasma phosphate level

  
• When plasma phosphate is high

  • Lower plasma free Ca+2 level
  • Stimulates PTH secretion
  • Inhibits 1,25(OH)2D3 formation

  
• Role of Magnesium


  • Requires for marinating normal parathyroid secretory responses
  • In magnesium deficiency there is: Impaired PTH release, Diminished target organ (bone & kidney) response to PTH, Results in hypocalcemia