Ca++ absorbed into blood Calcium homeostasis kidney Ca++ lost in urine bone 1000 g Ca++ stored in bone calcium deposition Blood Ca++ calcium resorption Ca++ absorbed into blood Why is calcium homeostasis important? 1. One of the major intracellular messengers (draw cell with high Ca++ outside, low Ca++ inside) a. Precise levels necessary for muscle contraction b. Responsible for exocytosis of secretory granules in neuronal synapses c. Serves as second messenger in many cells 2. Ca++ is necessary for blood clotting When would Ca++ levels change? after a large meal during a growth spurt during pregnancy or lactation Blood: Ca++ level usually 10 mg/100 ml (so 500 mg total in plamsa = 0.5 g) Regulation of calcium levels occurs in three different organs: bone, kidney, and small intestine small intestine: ingestion of Ca++ in food, taken up across the gut kidney: Ca++ is filtered through the nephron, and can be excreted in the urine bone: major storage site for Ca++ Calcium in the diet small intestine calcium lost in feces

Ca++ absorbed into blood Calcium homeostasis storage kidney Ca++ lost in urine bone calcium deposition Blood Ca++ calcium resorption 1000 g Ca++ stored in bone Ca++ absorbed into blood Think of it this way: Calcium is ingested through the gut (get more Ca++ into system) Calcium is secreted out of the body through the urine and the feces Calcium is stored in the bones To understand how calcium regulation occurs at the bone, we need to understand how bones work… intake excretion Calcium in the diet small intestine calcium lost in feces

Calcium cycling in bone tissue Bone formation Osteoblasts Synthesize a collagen matrix that holds Calcium Phospate in crystallized form Once surrounded by bone, become osteocyte Bone resorption Osteoclasts Change local pH, causing Ca++ and phosphate to dissolve from crystals into extracellular fluids Two processes: bone formation and bone resorption, going on continuously Calcium phospate crystals called ‘hydroxyapatite’ surface of crystals can exchange Ca++ and phosphate ions with extracellular fluid Write on board: -osteoblasts: builds bone (takes up Ca++ into bone) -osteoclasts: breaks down bone (removes Ca++ from bone) Now that we understand how calcium cycling happens at the bone, we can go back to the overall picture

Ca++ absorbed into blood Calcium homeostasis kidney Ca++ lost in urine bone calcium deposition Blood Ca++ calcium resorption Ca++ absorbed into blood Three hormones that affect regulation of calcium in the blood (write on board) Calcitonin Parathormone 1,25 Vitamin D3 Calcium in the diet small intestine calcium lost in feces

Hormonal Regulators Calcitonin (CT) Parathormone (PTH) 1,25 Vitamin D3

Calcitonin (CT) Secreted from the C cells in the thyroid Lowers Ca++ in blood Promotes deposition of Ca++ into bone (inhibits osteoclasts) Control of secretion from c-cells: CT CALCITONIN (CT) -Secreted from the C-cells in the thyroid gland -Lowers Ca++ in blood -Promotes deposition of Ca++ into bone -actually inhibits bone resorption in osteoclasts (ask them what osteoclasts do) -control of secretion: -increased plasma Ca++ stimulates C-cells to synthesize and release CT -Ca++ receptor on the cell membrane (draw on board!!) -when Ca++ binds the extracellular domain, activates Gs protein—Adenylate Cyc--increasing Camp -CT action needed -after meals, to prevent post-prandial hypercalcemia -gastrin (secreted in response to food in the stomach) also stimulates CT secretion -CT also important during pregnancy and lactation, to protect mother from Ca++ demands of fetus

Hormonal Regulators Calcitonin (CT) Parathormone (PTH) 1,25 Vitamin D3 Lowers Ca++ in the blood Inhibits osteoclasts Parathormone (PTH) 1,25 Vitamin D3

Parathormone (PTH) Increases Ca++ in blood Increases Ca++ resorption from the bone Stimulates osteoclasts Increases number of osteoclasts Increases Ca++ resorption from nephron Control of secretion: Necessary for fine control of Ca++ plasma levels PARATHORMONE (PTH) -secreted from cells of the parathyroid glands (chief cells) -increases Ca++ in the blood -remove the gland, plama Ca++ levels plummet, tetanic convulsions and death result -increases Ca++ resorption from the bone (how could it do that?) -stimulates the osteoclasts -increases the number of osteoclasts -increases Ca++ resorption from the pre-urine filtrate in the nephron (draw this!) -Control of secretion: -low extracellular Ca++ causes PTH release -Similar Ca++ receptor as found with CT (how does this work?) -except, when bound by Ca++, activates Gi protein, inhibiting cAMP levels, which decreases PTH secretion -PTH action needed for fine control of plasma Ca++ levels

Hormonal Regulators Calcitonin (CT) Parathormone (PTH) 1,25 Vitamin D3 Lowers Ca++ in the blood Inhibits osteoclasts Parathormone (PTH) Increases Ca++ in the blood Stimulates osteoclasts 1,25 Vitamin D3

1,25 Vitamin D3 UV Increases Ca++ uptake from the gut Increase transcription and translation of Ca++ transport proteins in gut epithelium Minor roll: also stimulates osteoclasts Increase Ca++ resorption from the bone UV Cholesterol precursor 7-dehydrocholesterol Vitamin D3 25 Vitamin D3 1,25 Vitamin D3 -made in the liver, the skin, the liver, and the kidney Liver: cholesterol precursor transformed to 7-dehydrocholesterol Skin: UV transforms 7-dehydrocholesterol to Vit D3 Liver: Enzyme transforms Vit D3 to 25-OH-Vit D3 Kidney: Enzyme transforms 25-Vit D3 to 1,25 Vit D3 -lack of melanin pigment in Northen Europeans was thought to account for the lower light level: let more UV across the skin to ensure high enough levels of Vit. D3 -increases Ca++ uptake from the gut -made from cholesterol…….acts like a steroid…..what kind of receptors? How would they act? (they increase transcription and translation of Ca++ transport proteins in the epithelial cells of the gut) -minor roll: also acts to stimulate osteoclasts, (which would do what?) increasing Ca++ resorption from the bone -control of secretion: -low Ca++ levels causes increase of PTH, which increases enzymes in the kidney (more enzyme, more 1,25 Vit. D3) 1,25 Vitamin D3 Low plasma Ca++ increase kidney enzymes

Hormonal Regulators Calcitonin (CT) Parathormone (PTH) 1,25 Vitamin D3 Lowers Ca++ in the blood Inhibits osteoclasts Parathormone (PTH) Increases Ca++ in the blood Stimulates osteoclasts 1,25 Vitamin D3 Increase Ca++ uptake from the gut

Calcium homeostasis kidney bone Blood Ca++ small intestine 1,25 Vit. D3 (+) 1,25 Vit D3 Ca++ PTH Parathormone (+) Calcitonin (-) Blood Ca++ resorption deposition Define osteoblasts (builders) and osteoclasts (resorbers) again Calcitonin Parathormone Vit D3 Other hormonal regulators of Ca++ homeostasis: Estrogens -stimulate osteoblast activity , limits osteoclast activity, and enhance PTH secretion -although there is a lot of disagreement on what estrogens do exactly in bone   -estrogens changes the set point of PTH cells in the parathyroid so a greater reduction of Ca++ is needed to increase PTH secretion (so E2 decreases Ca++ loss from bones) Clinical aspects: -(there are not many clinical problems with Ca++, because it rapidly leads to death) -Osteoporosis: decalcification and loss of bone matrix from the skeleton -maximum bone mass is achieved in women at age 35 -in the 30 years after menopause, women lose 30-50% of their bone mass -more common in women than men, may be because women have smaller bone calcium reserves -treatment: -estrogen replacement -increased Ca++ in the diet (slow down Ca++ turnover from bone) -exercise (especially weight bearing activities) stimulates bone deposition raquet arm of tennis players is 35% more dense than other arm Ca++ small intestine Ca++