10 22 12 Calcium Homeostasis Hormonal Control of Calcium Homeostasis Calcium homeostasis is important because all physiological processes directly or indirectly involve calcium ions Ca2 Directly Indirectly blood clot formation muscle contraction through the activation of an enzyme to catalyze a reaction Thus the calcium ion levels are maintained strictly between 9 mg 11 mg 100cc of blood normocalcemic The body will fight to maintain calcium levels When the blood levels rise above 11mg 100cc of blood hypercalcemia When the blood levels fall below 9mg 100cc of blood hypocalcaemia 99 of Ca2 is stored in the bone tissue as calcium phosphate crystals called hydroxyapatites o Need to break down bone and utilize free calcium for the biological response 2 hormones involved in maintaining calcium homeostasis are associated with the thyroid gland Parathyroid hormone PTH released by the parathyroid glands embedded in the posterior aspect of the thyroid hormone o Parathyroid glands appear as 4 glands secreting PTH referred to as chief cells Calcitonin released by the parafollicular cells also known as C cells in the thyroid gland Three hormones are responsible for maintaining normal calcium levels 1 PTH 2 Calcitonin 3 1 23 dihydroxy vitamin D 1 25 OH 2 Vit D Parathyroid hormone PTH Major stimuli for PTH release concentrations 84 amino acid peptide hormone released by chief cells inside the parathyroid glands appear as 4 glands o Hypocalcaemia PTH is released because calcium levels are too low and PTH stimulates increase in calcium blood o Hyperphosphatemia PTH is released because phosphate levels are too high and PTH acts to decrease phosphate levels in blood by increasing phosphate PO4 excretion by the kidneys leaving behind ionic Ca PTH release from chief cells requires the presence of Magnesium hence hypomagnesaemia is associated with Hypoparathyroidism PTH binds to PTH receptors on the surface of target cells to activate the cyclic AMP dependent signal transduction mechanism Gsalpha dissociation Biological Actions of PTH Targets Bones phosphate ions PTH indirectly activates osteoclasts to stimulate bone resorption resulting in the release of calcium and Osteoclasts lack PTH receptors so that PTH stimulates osteoclasts indirectly through the use of OAFs Osteoblasts express PTH receptors hence PTH binds to PTH receptors on osteoblasts and stimulate the osteoblasts to secrete osteoclast activating factors OAFs OAFs will then activate osteoclasts to stimulate bone tissue resorption breakdown bone to release calcium phosphate into the blood 1 2 o BUT if the calcium is bound to phosphate it is not going to contribute to the free calcium levels in the blood Targets the Kidneys 1 Phosphate PO4 excretion PTH stimulates the excretion of phosphate ions by the kidneys phosphaturia PTH binds to cells in the DCT distal convoluted tubules and the collecting ducts to stimulate 2 things a This drops the phosphate levels in the blood which prevents calcium phosphate crystals from depositing in tissues organs so that you see an increase in the calcium levels in the blood by taking the anion in the salt away 2 Calcium Ca2 reabsorption PTH inhibits calcium excretion and stimulates calcium reabsorption so that calcium is absorbed back into the blood Targets Vitamin D hydroxyvitamin D to the more active form 1 25 hydroxyvitamin D AKA 1 25 OH 2 Vit D which is the only hormone that stimulates calcium absorption from the small intestine PTH activates 1 alpha hydroxylase an enzyme produced by the kidneys which converts 25 o Enzyme 1 alpha hydroxylase catalyzes the conversion of 25 OH Vit D to 1 25 OH 2 Vit D which is the most active form of vitamin D Synthesis of 1 25 OH 2 Vit D cholecalceferol Vitamin D is a misnomer we now know that the active form of vitamin D can be made through the skin and does not need to be taken in through the diet 7 dehydrocholesterol in skin is converted to D3 by sunlight exposure then the enzyme 25 hydroxylase in liver converts D3 into 25 hydroxyvitamin D As 25 hydroxyvitamin D goes through the kidneys 1 alpha hydroxylase will add a hydroxyl group to the first position to get 1 25 dihydroxy vitamin D the most active form which binds to vitamin D nuclear receptors to form a heterodimer and exert its biological actions Vitamin D can also be taken in from various food sources in the form of D2 which is also converted to 25 hydroxyvitamin D by 25 hydroxylase in the liver and then converted into the active form 1 25 dihydroxy vitamin D by 1 alpha hydroxylase in the kidney Biological Actions of 1 25 OH 2 Vit D 1 25 OH 2 Vit D is a form of a steroid hormone and binds to Vitamin D receptors which are nuclear receptors that form heterodimers with RXR at the VDRE vitamin D responsive element of the target genes 1 25 OH 2 Vit D binds to its receptors in the small intestine to stimulate calcium absorption into blood directly absorbs calcium and phosphate ions from the GI tract from the diet into blood o 1 25 OH 2 Vit D is the only hormone that can absorb Ca2 from the GI tract in the small intestine 1 25 OH 2 Vit D synergizes with PTH to stimulate calcium reabsorption from the kidneys Under hypocalcaemic conditions when PTH is present 1 25 OH 2 Vit D synergizes with PTH to stimulate bone resorption so that PTH along with 1 25 OH 2 Vit D will work together to stimulate bone reabsorption o Hence 1 25 OH 2 Vit D taken without an adequate intake of calcium will result in bone resorption which can predispose you to developing osteoporosis Under hypercalcemic conditions when PTH is absent 1 25 OH 2 Vit D activates the osteoblasts to stimulate bone tissue secretion and the mineralization of bone tissue by calcium phosphate crystals bone formation and hence Increase in bone density results Hence 1 25 OH 2 Vit D is basically interested in maintaining a normocalcemic condition it does not matter if this involves bone reabsorption or bone formation Dysfunction of PTH HYPERFUNCTION HYPERPARATHYROIDISM Types o Primary Hyperparathyroidism Cause Tumor of the parathyroid glands o Secondary Hyperparathyroidism Cause Ectopic production of PTH or PTH related peptides PTHrP from cancers which acts as agonists to stimulate PTH biological actions PTHrP act just like PTH by binding to PTH receptors Clinical Features of Hyperparathyroidism Hyperparathyroidism Excess bone resorption hypercalcemia osteoprorsis Clinical features of hyperparathyroidism clinical features of hypercalcemia Hypercalcemia too much calcium in the