9/1/2012 Calcium balance Importance of calcium
• in vertebrates plays double role:
– in the form of inorganic salts (hydroxyapatite) builds up the internal frame (skeleton)
– found in the extracellular space in soluble form
• calcium metabolism is strictly regulated as its appropriate level is indispensable in many physiological processes
– sets the threshold of voltage-dependent Na+-channels – low Ca++ level: increased excitability, spontaneous contractions, tetanus
– exocytosis – synapses, gland cells – action potentials in the heart and smooth muscles – muscle contraction – hemostasis (blood clotting)
• half of the Ca++ in the blood is bound to proteins, part of the rest is bound to anions, free, ionized concentration is: 1,1-1,2 mmol/l
• during alkalosis (e.g. hyperventilation) – more negative charges on proteins – increased binding of Ca++ to proteins – Ca++ level decreases - increased excitability of neurons and muscles 9/1/2012 Calcium metabolism external turnover internal turnover intracellular absorption extracellular interstitial fluid in bones secretion ry nta e lim glomerulal mineralized filtration reabsorption urine 200 mg Bone tissue
• our body contains about 1-2 kg calcium, of this 99% in bones
• remodeling is continuous in bones, it can restore diminished plasma level if necessary
• remodeling is regulated by several hormones: parathyroid hormone, calcitriol (vitamin D), calcitonin, androgens (estrogens), glucocorticoids
• osteoprogenitor – osteoblast – matrix synthesis (collagen, etc. fibers) – osteoid tissue
• osteoblasts surrounded by the matrix become osteocytes; keeping contact with each other through thin processes
• the next step is mineralization or calcification a – hydroxyapatite precipitates on the fibers
• precipitation is induced by an increase of phosphate concentration – phosphatase and pyrophosphatase activity of osteoblasts release phosphate from organic and inorganic phosphates 9/1/2012 Remodeling of the bone
• osteoclasts are giant, multinucleated macrophages
• they are activated by paracrine factors released by the osteoblasts and other local influences (TNF, IL-1, etc.)
• secretion of H+-ions and hydrolyzing enzymes – dissolution of the hydroxyapatite and the
• remodeling goes according the “brick wall model” - triggering effect is unknown
• osteoclasts bore cavities into the bone (7-10 days), osteoblasts synthesize the matrix, then mineralization follows
• in young people rebuilding is 100%, later not: osteoporosis
• androgens facilitate, glucocorticoids inhibit rebuilding
• matrix contains cytokines freed during dissolution of the bone – they inhibit this process and facilitate rebuilding Parathyroid hormone (PTH) 6/13
• in humans produced by 4 parathyroid glands (40 mg each) located in the thyroid gland
• deletion of the thyroid gland – death in humans, in some species auxiliary parathyroid glands
• cells here and in many other tissues also produce PTH-related-peptide – paracrine role
• pre-pro-PTH (115) – pro-PTH (90) – PTH (84) • production is regulated by the Ca++ level in the blood through negative feedback (fast)
• very sensitive between 1-1,3 mmol/l, higher or lower levels cause no additional change
• Ca++ level is detected by G-protein associated 7TM receptors – low level – cAMP synthesis – PTH release
• another, slower element of the regulation is calcitriol (vitamin D) 9/1/2012 Regulation of PTH production parathyroid gland cell distal tubule in kidney proximal tubule 1-α-hydroxylase calcitriol Effects of parathyroid hormone
• its main effect is to increase the Ca++ level in the blood
• acts mainly on the kidneys and the bones • kidney
– Ca++ reabsorption increases in distal tubules – P-reabsorption decreases in the proximal tubules – 1-α-hydroxylase activity is facilitated in proximal
– Ca++ permeability of osteocyte processes forming a barrier between the capillaries and the interstitial fluid increases (2-3 hours)
– osteoblasts activate osteoclasts (they have no PTH receptor) through paracrine mediation (after 12 hours)
– immature osteoclasts differentiate into maturate osteoclasts
• high PTH level: osteolysis, low level: tetanus 9/1/2012 Parathyroid hormone effects osteoclast precursor osteoblast mature osteoclast osteocyte permeability P-reabsorption in proximal 1-α-hydroxylase in proximal calcitriol Ca++ reabsorption in distal tubule Calcitriol (vitamin D)
• vitamin D is known in two forms:
– ergocalciferol, D2 – uptake with food – cholecalciferol, D3 – uptake with food (cod liver oil), or produced in the skin from 7-dehydrocolesterol under the influence of UV irradiation (sunshine)
• vitamin D is only missing, if there is no uptake with food and there is no sunshine either
• calciferols are inactive – they are transformed in an unregulated way (possibility of overdosing) in the liver to 25-OH-calciferol, which has weak activity
• additional OH at position 1 in the kidney in a regulated way – calcitriol
• regulation:
– negative feedback at 3 points – alternate hydroxylase binding OH to position 24, rendering the molecule inactive 9/1/2012 Effects of calcitriol
• calcitriol effects can be grouped in 3 categories:
– increase of blood Ca++ level – effects on bones and other tissues – inhibition of its own production and that of PTH
• increase of Ca++ level mainly through facilitating reabsorption from the alimentary canal – in addition, weak facilitation of active transport in the renal distal tubules
• in the bones it effects osteoblasts and immature osteoclasts, similarly to PTH
– influences mineralization of osteoid tissue – in high concentration stimulates osteoclasts through factors released by osteoblasts
– facilitates the maturation of immature osteoclasts
• lymphocytes and monocytes posses calcitriol receptors – modulation of immune functions Calcitriol effects osteoclast precursor osteoblast mature osteoclast enterocyte absorption calcitriol reabsorption in distal tubules parathyroid secretion immunocytes 9/1/2012 Calcitonin
• gene is present in various cells – alternate splicing – different products:
– in C-cells distributed diffusely in the thyroid gland – calcitonin precursor
– in nerve cells and other cells „calcitonin-gene- related-peptide”, CGRP – acting as transmitter
• precursor (124) – calcitonin (32) • production regulated directly by blood Ca++ level through G-protein associated 7TM receptor – higher level – increased cAMP synthesis – increased calcitonin secretion
• calcitonin acts on 7TM receptors, activating several G-protein pathways – cAMP increase, protein kinase C activation
• osteoclast inactivation - decreased Ca++ level • in addition, decreased Ca++ reabsorption, increased excretion in the kidney
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