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Calcium homeostasis

Calcium homeostasis. Bone remodeling and repair. Continuous remodeling 5 to 7 % of total bone mass per week Critical for maintenance of proper structure Removal of calcium. Bone remodeling. Location Periosteum Endosteum Remodeling units Osteoblasts Osteoclasts Does not occur uniformly

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Calcium homeostasis

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  1. Calcium homeostasis

  2. Bone remodeling and repair • Continuous remodeling • 5 to 7 % of total bone mass per week • Critical for maintenance of proper structure • Removal of calcium

  3. Bone remodeling • Location • Periosteum • Endosteum • Remodeling units • Osteoblasts • Osteoclasts • Does not occur uniformly • Different bones/different rates

  4. Bone remodeling • Deposit • Site of injury • Strength re-enforcement • Nutrients • Proteins • Vitamins (A and D) • Minerals

  5. Bone remodeling • Deposit • Osteroid seam • New matrix deposit • Unmineralized bone • Calcification front • Rate of calcification • Local concentrations of mineral products • Matrix proteins • Alkaline phosphatase

  6. Bone remodeling • Resorption • Break down of bone matrix • Formation of resorption bay • Osteoclasts • Lysosomal enzymes • HCL • Phagocytosis of dead osteocytes • Activation triggered by T-lymphocytes

  7. Regulation • Feedback loops (Whether and when) • Calcium homeostasis in the blood • Parathyroid hormone (PTH) • Elevates blood calcium concentration by increasing resorption • Calcitonin • Increase calcium deposition by osteoblasts

  8. Parathyroid gland • Embedded on the thyroid surface • Four in humans • Located in the back of thyroid glands

  9. Removal of thyroid gland • Lethal • Removal of parathyroid glands • Decrease in blood calcium level • Tetanic convulsion and death

  10. Cell composition • Chief cells • Secretes parathyroid hormone • Oxyphil cells • Unknown functions Oxyphil cells

  11. Parathyroid hormone • Essential for life • Chemistry • 84 AA • Preprohormone (115 AA) • Synthesized and converted within the Golgi zone of the chief cells • Proteolytic cleavage yields 90 AA prohormone • prohormone • Removal of 6 AA to yield mature peptide • Released into the bloodstream via exocytosis

  12. Highly conserved hormone • Short half-life • 3-4 min • Cleaved into two fragments

  13. Regulation of secretion • Blood calcium level • Ca receptors on the parathyroid cells • Seven-transmembrane domain receptor • Coupled with G-protein complex • Highly conserved • 93 % AA homology between human and bovine receptors • Interaction of receptor with Ca • Concentration- dependent conformation alteration • Decreased cAMP production when high Ca concentrations • Increased cAMP production when low Ca concentrations

  14. Vitamin D • Inhibition of PTH secretion • Genomic level • Slow effects • No changes in release of PTH immediately after vitamin D treatment

  15. Function of PTH • Elevation of blood calcium level • Decreased phosphate ion concentrations • Acts on kidneys, intestines, and bones • Effects on mineral metabolism • Increased osteoclast activity • Secretion of cytokines by stromal osteoblast in response to PTH • Demineralization of bones

  16. Renal excretion and reabsorption • Increased calcium reabsporption • Renal tubular reabsorption • Increased phosphate excretion (phosphaturia) • Increased ionization of calcium • Prevention of CaPO4 formation • Increased Mg reabsorption • Inhibition of Na-H exchange • Decreased blood pH • Inhibition of Ca binding to plasma proteins

  17. Absorption of calcium • Intestine • Increased uptake (direct) • Effects on vitamin D metabolism (indirect) • Control of vitamin D synthesis • Increased 1,25-dihydrovitamin D synthesis from vitamin D • Kidney

  18. Other actions • Increased reticulocyte and lymphocyte mitosis • Vasodilation • Direct action involving specific receptor

  19. Mechanism of action • Interaction between PTH and its receptor • Increased cAMP production • Gs • Activation of phospholipase C • Production of IP3 and DG • Activated by Gq • Vitamin D-dependent • Mobilization of Ca from bones

  20. Role of vitamin D on PTH action • Not on cAMP production • Normal cAMP production by the bones from vitamin D deficient mice • Later parts of biochemical reactions

  21. Calcitonin • Maintenance of blood Ca level • Critical • Acute elevation • Meal • Return to normal shortly after elevation • Role of thyroid gland • Secretion of calcitonin • C (clear) cells

  22. Synthesis and metabolism • 32 AA • Derived from larger prohormone • Ring structure • Disulfide bridge between AA 1 and AA 7 • Isoforms • Two • I in combination with II or III

  23. High structural similarity • Low AA homology • Fish calcitonin is more potent in humans • Resists proteolytic digestion • Higher receptor affinity

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