Control of Mineral Metabolism (and other nonsense)

Question 1

Physiological roles for calcium (2)

Answer 1

• Structural
  
  • Major constituent of mineral matrix of bone
  • Serves as reservoir for maintenance of plasma calcium
• Biochemical
  
  • Essential regulator of:
    
    • Excitation-contraction coupling
    • Stimulus-secretion coupling
    • Blood clotting
    • Membrane excitability
    • Cellular permeability
    • Other metabolic function

Question 2

Physiologic roles of phosphate (2)

Answer 2

• Structural
  
  • Part of mineral matrix of bone
• Biochemical
  
  • Required for:
    
    • Phosphorylation reactions (transfer of energy in form of high energy phosphate groups)
    • Intracellular buffer
• 85% of serum phosphate free in ionized active form of HPO₄^2-and H₂PO₄^2-

Question 3

3 major compartments involved in calcium & phosphate homeostasis

Answer 3

• Bone
  
  • 99% of calcium in form of hydroxyapatite
• Intracellular compartment
  
  • 10 g = ~50-100 nM in resting cell
  • Cytosolic calcium level maintained by pumping calcium into ER for storage by ATP-linked pump and Na/Ca antiporter
• Extracellular compartment (includes blood and interstitial space)
  
  • 2.5mM
  • 50% calcium in free form, filtered by kidney
  • 10% in salts (bicarbonate and phosphate)
  • Remainer bound to albumin
  • Kidney filters 10g/day - 98% reabsorbed

Question 4

Regulation of PTH release

Answer 4

• From 4 parathyroid glands
• Regulated by typical negative feedback loop
  
  • Serum calcium = regulated variable
• PTH made by chief cells in parathyroid gland
  
  • Released via Ca2+ dependent exocytosis
• Increased serum Ca2+ –> decreased PTH release from parathyroid
• Decreased serum Ca2+ –> increased PTH release from parathyroid

Mechanism:

• Decreased serum Ca2+ –> increased intracellular Ca2+ via calcium sensor protein
• When serum Ca2+ decreases, sensor protein hooks up with Gq protein –> part of G protein subunit heads to ER and causes release of Ca2+ via IP3

Question 5

Action of PTH

Answer 5

• PTH = Phosphate Trashing Hormone
• Bone: fast and slow response to PTH
  
  • Fast: efflux of labile bone calcium with no phosphate release from bone (encourages osteocytic osteolysis)
  • Slow: increased bone remodeling with release of both bone calcium and phosphate (usually pathologic)
• Kidney:
  
  • Increased Ca2+ reabsorption in distal tubule
  • Decreased phosphate reabsorption (CaPO4 has very low solubility - body doesn’t want it)
  • Increased synthesis of 1,25 (OH)₂ Vitamin D
• GI tract: indirect by way of vitamin D
  
  • Increased Ca2+ absorption (requires a day)
  • Increased phosphate absorption

Question 6

Synthesis of vitamin D

Answer 6

• Making active vitamin D
  
  • In skin: 7-dehydrocholesterol + sunlight = vitamin D3
  • D3 travels to liver –> converted to 25(OH) vitamin D3
  • 25(OH) D3 then activated in kidneys by 1a-hydroxylase –> turned into 1,25 (OH)₂ D3
• Alternatively:
  
  • Kidney can produce inactive form 24,25(OH)₂ vitamin D by 24-hydroxylase activity
    
    • In equilibrium with active form
  • In absence of PTH, 24-hydroxylase is more active
• 1,25 (OH)₂ vitamin D transported in serum by binding to transcalciferin

Question 7

Regulation of vitamin D

Answer 7

• Increased PTH –>
  
  • Increased 1a-hydroxylase activity and decreased 24-hydroxylase activity –> more active vitamin D to absorb Ca2+ from GI tract
• Decreased phosphate –>
  
  • Increased 1a-hydroxylase activity and decreased 24-hydroxylase activity –> more active vitamin D to absorb phosphate from GI tract
• Decreased [Ca2+] –> Increased PTH –> Increased 1,25(OH)₂ vitamin D production
• Decreased phosphate causes 1,25(OH)₂ vitamin D production
• Cortisol decreases vitamin D action
• Estrogen + growth factors work opposite of PTH and drive Ca2+ into bone

Question 8

Actions of vitamin D

Answer 8

• Increased absorption of dietary calcium
• Increased absorption of dietary phosphate
• Increased bone resorption of Ca2+ and phosphate (mechanism unknown)

Question 9

Regulation of serum calcium

Answer 9

• Short-term: primarily PTH
• Long-term: vitamin D-mediated GI absorption of calcium and phosphate
• Decreased serum Ca2+ –> increased excitability –> muscle twitches, seizures
  
  • Cellular (-) surface charges are screened by Ca2+
• Increased serum Ca2+ –> decreased excitability –> sluggishness

Question 10

Calcium in the body

Answer 10

• In blood: transported on albumin (50%), salts (10%), free (40%)
• Rapid process under normal circumstances, Ca2+ in cannalicular fluid lower than serum Ca2+
  
  • Ca2+ flows into cannalicular fluid down concentration gradient, taken up by osteocytes
  • Osteocytes pump calcium out through long processes back to surface osteoblasts and back into blood
  • Rapid calcium exchange = osteocytic osteolysis
    
    • Causes 10g to be cycled daily
• Slower process: exchange of 280mg of Ca2+ through bone resorption
• Phosphate only undergoes slow exchange due to remodeling - no rapid process

Question 11

3 important cell types in bones

Answer 11

• Surface osteoblasts
• Osteocytes
• Osteoclasts