10/22/12Calcium HomeostasisHormonal Control of Calcium Homeostasis- Calcium homeostasis is important because all physiological processes directly or indirectly involve calcium ions (Ca2+)- Directly - blood clot formation, muscle contraction- Indirectly -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 hydroxyapatiteso 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 hormoneo 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. PTH2. Calcitonin3. 1,23 dihydroxy vitamin D (1,25(OH)2 Vit D)Parathyroid hormone (PTH)- 84 amino-acid peptide hormone released by chief cells inside the parathyroid glands (appear as 4 glands)-Major stimuli for PTH release:o Hypocalcaemia- PTH is released because calcium levels are too low and PTH stimulates increase in calcium blood concentrationso 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 : PTH indirectly activates osteoclasts to stimulate bone resorption resulting in the release of calcium and phosphate ions 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 bloodo 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 : PTH binds to cells in the DCT (distal convoluted tubules) and the collecting ducts to stimulate 2 things:1. 1. Phosphate (PO4) excretion- PTH stimulates the excretion of phosphate ions by the kidneys= phosphaturia 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 away2. 2. Calcium (Ca2+) reabsorption- PTH inhibits calcium excretion and stimulates calcium reabsorption so that calcium is absorbed back into the blood- Targets Vitamin D: PTH activates 1 alpha hydroxylase, an enzyme produced by the kidneys, which converts 25 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 intestineo 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 DSynthesis of 1,25 (OH)2 Vit D= cholecalceferolVitamin 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 andexert 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 kidneyBiological 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 bloodo **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 reabsorptiono 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 formationDysfunction of PTH: HYPERFUNCTION= HYPERPARATHYROIDISM- Types:o Primary Hyperparathyroidism  Cause: Tumor of the parathyroid glandso Secondary Hyperparathyroidism  Cause: Ectopic production of PTH or PTH-related peptides (PTHrP) from cancers which acts as agonists tostimulate PTH biological actions- PTHrP act just like PTH by binding to PTH receptorsClinical Features of Hyperparathyroidism:-