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 –Different bones/different rates

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

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

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

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

Parathyroid gland Embedded on the thyroid surface –Four in humans Located in the back of thyroid glands

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

Cell composition –Chief cells Secretes parathyroid hormone –Oxyphil cells Unknown functions Oxyphil cells

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

Highly conserved hormone Short half-life –3-4 min –Cleaved into two fragments

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

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

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

Renal excretion and reabsorption – Increased calcium reabsporption Renal tubular reabsorption –Increased phosphate excretion (phosphaturia) Increased ionization of calcium –Prevention of CaPO 4 formation –Increased Mg reabsorption –Inhibition of Na-H exchange Decreased blood pH –Inhibition of Ca binding to plasma proteins

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

Other actions –Increased reticulocyte and lymphocyte mitosis –Vasodilation Direct action involving specific receptor

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

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

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

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

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