CALCIUM HOMEOSTASIS Bone, 3 hormones (PTH, Vitamin D and Calcitonin) Calcium in the body 1.1 1.

.3 kg of Ca++ in body - 99% = skeletal - 0.9% is intracellular - 0.1% is extracellular Typical plasma concentration = 9-11mg/dL, 2.5mM 50% bound to albumins (binding is pH dependent, acute alkalosis increases binding), globulins, phosphate and citrate 50% free, biologically active

Intracellular concentration = 100nM Massive chemical transmembrane gradient Found mostly as protein complexes in membrane or ER

derived from dietary sources Importance of calcium Calcium phosphate salts in bone provide structural integrity of the skeleton Ions in extrac and intrac fluids are essential for normal function of several biochemical processes e.g. neuromuscular excitability, blood coagulation, hormonal secretion, enzymatic regulation

e.g. Neuromuscular excitability 1. 2. Hypocalcemia Increased membrane Na+ permeability Nerves & muscles overexcitable Tetany involuntary muscular spasms Larngospasms airway constriction Hypercalcemia Decreased neuromuscular sensitivity Groans, constipation Bone pain Kidney stones Cardiac arrhythmias

Importance of phosphate Essential for normal function of several cellular processes e.g. signal transduction Important structural role in the cell e.g. DNA/RNA, membrane phospholipids, complex carbohydrates

Ca++ homeostasis minute to minute monitoring/adjustment of plasma levels to maintain them within the normal range Ca++ balance long term, refers to relative rates of Ca++ bone deposition or resorption

Bone Bone is an NB reservoir of Calcium storage (99% total body). In bone remodeling, about 10% of total adult bone turns over each year. In growth, rate of bone resorption exceeds resorption and skeletal mass increases. Linear growth occurs at epiphyseal plates while width increases at periosteum. At about 30 years, rate of absorption begins to exceed formation and bone mass slowly decreases. Structure and cells: Osteoblasts (bone formation) differentiated bone forming cells which secrete bone matrix/collagen on Ca++ and phosphate precipitate Osteocytes (bone maintenance) osteoblasts/mature bone cells enclosed in matrix Osteoclasts (bone resorption) large multinucleated cell derived from monocytes Osteogenic cells immature bone stem cells that proliferate to give osteoblasts

Bone remodeling resorption and formation Dynamic tissue Rates of resorption and formation normally in EQ Differential activity of osteoblasts/clasts determine bone formation/loss These cells are targets for several endocrine and paracrine regulators of Ca++ homeostasis

Osteoblasts and their role in osteoclast development Produce 2 NB mediators for osteoclast development 1. RANKL (receptor activator of NF ligand) TNF cytokine family Binds to RANK on macrophages and promotes differentiation into osteoclasts and suppression of apoptosis Increased resorption 2. Osteoprotegrin Inhibitor/decoy receptor for RANK Decreases resorption

mechanism of resorption: 1. Osteocytic osteolysis (rapid exchange) - Ca++ is moved from labile pool in bone fluid into plasma by PTH activated Ca++ pumps - Pumps located in osteocytic-osteoblastic bone membrane (filmy intercytoplasmis projections of the 2 cells) 2. Osteoclastic resorption (slow exchange) - Ca++ moved from stable pool in mineralized bone into plasma via PTH induced dissolution of the bone by osteoclasts

Hormonal control of Ca++ by Calcitrophic Hormones

Ca++ resorption, reabsorption and absorption is regulated in bone, kidney and intestine by PTH, Vitamin D3 and calcitonin Parathyroid Hormone What is it? Calcitrophic hormone, peptide Where is it made? Secreted by the parathyroid gland which lies posterior to the thyroid gland The chief/principal cells are Ca++ sensing

Synthesis Pre-prohormone in RER Cleavage of leader and pro-sequences in the golgi apparatus give biologically active peptide Proteolysis of PTH generates C terminal protein fragments that are inactive. This is NB for modulating amount of active PTH released Stored in secretory granule

Regulation of secretion Plasma free/ionized Ca++ is the main regulator Secretion is inversely related to Ca++ conc Max secretion when Ca++ is less than 3.5mg/dL Other regulators = catelcholamines, Mg++

Parathyroid calcium sensing receptor G protein coupled receptor on chief cells Gq increases IP3 (phospholipase C)

Gi decreases cAMP If ECF concentration increases, cAMP decreases and IP3 increases, PTH secretion decreases

Targets & Physiological role? To increase plasma Ca++ levels (& moderately decrease plasma phosphate) It acts directly on bones to increase resorption (2 mechanisms above) On the kidney to increase Ca++ reabsorption and phosphate excretion Indirectly on intestine by stimulating 1,25-(OH)2-D synthesis Ca++ feedback loop suppresses PTH

Association with any diseases? Inactivating mutationshypocalciuric hypercalcemia Activating mutationshypoparathyroidism/hypercalcuria/hypocalcemia

Vitamin D (Cholecalciferol): What is it? Not a classic hormone as it is not produced and secreted by an endocrine gland. But it is a true hormone because it has an endocrine mode of action of distant target via binding to high affinity receptors. Where is it made? 1. derived from photodependent production in keratinocytes 2. ingested in the diet skin: 7-dehydrocholesterol converted to Vitamin D3 liver: Vit D3 hydroxylated by P450C25 to 25(OH)D3/calcidiol kidney: 2nd hydroxylation reaction catalysed by 1 hydroxylase to produce calcitriol/1,25(OH)2D3 1 hydroxylase activity is regulated via feedback inhibition, PTH, hypophosphatemia and prolactin target tissue? intestine, bone, parathyroid, immune cells and some remains in kidney Physiological role? 1. Promotes intestinal calcium absorption Approximately 200mg of Ca++ is absorbed per day. The major site for absorption is the duodenum. Vesicular, transcellular and paracellular transport are all Vit D dependent Facilitated/active transport of Ca++ into enterocyte

bound by a Vit D inducing high affinity Ca++ binding protein called calbidin some Ca++ is stored in cell organelles while some is pumped out of cell by ATP dependent pump thus increasing Ca++ in the ECF

2. Actions on Bones - Osteoblasts have Vitamin D receptors - Stimulates release of RANKL from osteoblasts enhancing osteoclast differentiation and proliferation - Increases resorption Diseases? Vitamin D deficiency causes rickets Familial Vitamin D deficiency caused by mutation in vitamin D receptor

Calcitonin What is it? Belongs to evolutionary conserved family of hormones that includes islet amyloid precursor protein, calcitonin gene related peptide, adrenomedullin Where is it made? Produced in thyroid C cells (parafollicular cells) Different from follicular cells due to large size, pale cytoplasm, and small secretory granules

Regulation? Secreted in response to increased plasma Ca++ levels Physiological role? Minor role in calcium homeostasis and aims to decrease plasma levels Functional anatagonist to PTH Inhibit osteoclastic activity in bone Inhibit reabsorption at kidney