Regulation Of Calcium And Phosphorous PDF

Week 3.2: Regulation of Calcium Metabolism Learning Objectives:  Describe the mechanisms for the maintaining homeostasis of body calcium and phosphate concentrations  Describe the body stores of calcium, their rates of turnover, and the organs that play central roles in regulating movement of calc...

Week 3.2: Regulation of Calcium Metabolism Learning Objectives:  Describe the mechanisms for the maintaining homeostasis of body calcium and phosphate concentrations  Describe the body stores of calcium, their rates of turnover, and the organs that play central roles in regulating movement of calcium between stores.  Describe mechanisms of calcium and phosphate absorption and excretion.  Identify the major hormones and other factors that regulate calcium and phosphate homeostasis and their sites of synthesis as well as targets of their action.  Delineate cells of bone and their functions in bone formation and resorption Physiological Processes that involve Ca2+  Muscular contraction  Membrane permeability  Endocrine and exocrine secretions  Enzyme regulation  Coagulation Calcium Stabilizes Membrane Potentials  Hypocalcemia can lead to various manifestations of enhanced membrane excitability, including muscle spasms (tetany), cardiac arrhythmias, and seizures.  Hypercalcemia, on the other hand, reduces membrane excitability, leading to such manifestations as muscle weakness and stupor. Calcium regulation involves:  Three tissues ◦ Bone (and teeth), Intestine and Kidney  Three hormones ◦ PTH, calcitonin and activated vitamin D3  Three cell types ◦ Osteoblasts, Osteocytes and Osteoclasts Regulation of Calcium Metabolism  Parathyroid Hormone  Parathyroid Gland  Raises [Ca+2]  Calcitonin  Thyroid gland  Lowers [Ca+2]  Vitamin D  Absorption of Ca+2 (PTH) Calcium Regulation  PTH and Calcitonin regulate blood calcium levels  When calcium is high: ◦ Calcitonin is produced (“tones down”)  When calcium is low: ◦ PTH is produced Calcium Stores in The Body  The adult human body contains 1-1.3 kg of calcium.  Approximately 99 % of this is contained within bones and teeth.  The remaining 1 % is distributed between soft-tissue cells and extracellular fluid (i.e. interstitial fluid and blood plasma). Forms of Ca2+ in Blood Forms of Ca2+ in Blood  The total Ca2+ concentration in blood is 10 mg/dL  Bound Calcium: 40% of the total Ca2+, is bound to plasma proteins, mainly albumin  Ultrafilterable Calcium (60%) not protein-bound ◦ Complexed to anions (e.g., phosphate, sulfate, citrate) ◦ Free, ionized Ca2+ Free Ca2+ ionized Ca2+ is the only form of Ca2+ that is biologically active.  Free, Albumin – Ca++ Transport  40% of the total Ca2+, is bound to plasma proteins, mainly albumin  Albumin carries a negative net charge on its surface.  Albumin has negatively charged sites, which can bind either H+ ions or Ca2+ ions Acid-Base Abnormalities & [Ca2+]  Acid-base abnormalities alter the ionized Ca2+ concentration by changing the fraction of Ca2+ bound to plasma albumin  Albumin has negatively charged sites, which can bind either H+ ions or Ca2+ ions Acid-Base Abnormalities & [Ca2+] Acid-base Abnormalities & [Ca2+]  In acidemia ◦ an excess of H+ in blood  more H+ binds to albumin, leaving fewer sites for Ca2+ to bind. ◦ Free ionized Ca2+ concentration increases  In alkalemia ◦ a deficit of H+ in blood  less H+ will be bound to albumin, leaving more sites for Ca2+ to bind. ◦ Free ionized Ca2+ concentration decreases Roles of Calcium in Body  Signal Transduction (Neurotransmitter release)  Second messenger  Structural component in bone matrix  Muscle contraction  Bone Formation Ca2+ Balance  Renal & GI: Net excretion of Ca2+ by the kidney is equal to net absorption of Ca2+ from the gastrointestinal tract  Bone Remodeling ◦ New bone is formed (deposited) and old bone is resorbed. Bone resorption is stimulated by Parathyroid Hormone  Bone Absorption is stimulated by Vitamin D (1,25dihydroxycholecalciferol) and is inhibited by calcitonin. Role of Phosphate in the Body  Formation of adenosine triphosphate (ATP)  Phosphate can serve as a biologic buffer  Phosphate can act as a modifier of proteins, thereby altering their functions. The Parathyroid Glands & PTH The Parathyroid Glands  Embedded in posterior thyroid capsule  Parathyroid Hormone (PTH)  The chief cells of the parathyroid glands synthesize and secrete PTH  The role of PTH is to regulate the concentration of Ca2+ in ECF ◦ (i.e., plasma or serum) PTH – Calcium Levels  PTH promotes calcium release from bone tissue  PTH stimulates kidney to conserve calcium  Increase in blood calcium levels PTH functions to increase plasma calcium and to decrease plasma phosphate and bicarbonate Actions of PTH on bone, kidney, and intestine PTH & Calcium Levels   [Ca2+]  PTH PTH secretion is regulated by the plasma [Ca2+] Small decreases in result in ionized plasma [Ca2+] promotes large increases in the rate of PTH formation ◦ In contrast, an increase in plasma phosphorus concentration stimulates PTH release.  PTH promotes calcium release from bone tissue  Activates Osteoclasts  PTH stimulates kidney to conserve calcium (99% Reabsorption)  PTH stimulates phosphate (HPO4-2) excretion  PTH  Increase in blood calcium levels PTH – Calcium Levels  The major regulator of PTH secretion is ionized plasma Ca2+, although vitamin D also plays a role.  Both inhibit the synthesis or release of PTH.  In contrast, an increase in plasma phosphorus concentration stimulates PTH release. Actions of Parathyroid Hormone  PTH has actions on bone, kidney, and intestine, all of which are coordinated to produce an increase in plasma [Ca2+]  Bone ◦ Increased osteoclast activity  Kidney ◦ Increased reabsorption of Ca++  Intestine ◦ Activation of vitamin D  Increased absorption of Ca++ from SI PTH & Bone  In bone, PTH receptors are located on osteoblasts  Initially PTH causes an increase in bone formation by a direct action on osteoblasts  this action of PTH has been utilized in the treatment of osteoporosis.  PTH indirectly stimulates bone resorption by osteoclasts. PTH & Bone - Osteoclasts  PTH indirectly causes an increase in bone resorption ◦ Osteoclasts do not have PTH receptors.  Instead, PTH binds to receptors on osteoblasts and stimulates the osteoblasts to release factors (such as IL-6 and RANK ligand)  These factors promote bone resorption by osteoclasts.  Degradation of bone free up Ca++ Osteoclasts resorb bone in discrete areas in contact with the ruffled border of the cell PTH & the Kidney PTH & the Kidney  PTH has two actions on the kidney.  (1) PTH inhibits phosphate reabsorption  (2) PTH stimulates Ca2+ reabsorption Ca+2 PO4 +3 PTH & Phosphate Reabsorption Inhibition  Inhibiting Na+-phosphate cotransport in the proximal convoluted tubule of the nephron (phosphaturic action of PTH )  Phosphaturia - The phosphaturic action of PTH causes the phosphate that was resorbed from bone to be excreted in the urine  Excreting phosphate in urine “allows” the plasma ionized Ca2+ concentration to increase  phosphate would otherwise complex Ca2+ in ECF. Actions of Parathyroid Hormone PTH: Inhibition of phosphate reabsorption  PTH binds to its receptor on the cell membrane of target tissue. (Bone cell / Kidney Cell)  PTH receptor via G protein to adenylyl cyclase  cAMP  cAMP activates a series of protein kinases which phosphorylate intracellular proteins leading to inhibition of Na+-phosphate cotransport  Decreased phosphate reabsorption and phosphaturia PTH & Small Intestine  PTH Activation of Vitamin D Synthesis ◦ PTH does not have direct actions on the small intestine ◦ PTH indirectly it stimulates intestinal Ca2+ absorption via activation of vitamin D  PTH stimulates renal 1α-hydroxylase ◦ enzyme that converts 25-hydroxycholecalciferol to ◦ the active form, 1,25-dihydroxycholecalciferol (VIT D)  1,25-dihydroxycholecalciferol stimulates intestinal Ca2+ absorption When blood calcium concentration falls…  PTH formation increases, stimulating the activity of osteoclasts and causing movement of calcium from bone to ECF.  PTH increase causes a higher rate of formation of 1,25dihydroxycholecalciferol (active Vit D)  Elevated concentration of vitamin D stimulates the formation of calcium-binding protein and other factors in the epithelium of the small intestine, which increase the rate of absorption of calcium from the lumen of the gut. PTH & Vitamin D Vitamin D & PTH  Vitamin D, in conjunction with PTH, is the second major regulatory hormone for Ca2+ and phosphate metabolism.  PTH: Maintain plasma Ca2+ concentration  increase the ionized Ca2+ concentration toward normal levels  Vitamin D: promote mineralization of new bone ◦ increase both Ca2+ and phosphate concentrations in plasma so that these elements can be deposited in new bone matrix Vitamin D Synthesis  Skin  Liver  Kidney Vitamin D Synthesis  Vitamin D (cholecalciferol) is provided in the diet and is produced in the skin from cholesterol.  Vitamin D (cholecalciferol) is inactive and must be successively hydroxylated to an active metabolite. Sources of Vitamin D (cholecalciferol)  Dietary Sources ◦ Vitamin D is ingested in the diet  Synthesized in the skin ◦ Vitamin D is synthesized from 7-dehydrocholesterol in the presence of ultraviolet light. Vitamin D Formation – Skin  Vitamin D is made in the skin from cholesterol through a chemical reaction that is dependent on sun exposure (specifically UVB radiation). Vitamin D cholecalciferol In the skin, 7,8 - dehydrocholesterol is converted by ultraviolet light to vitamin D INACTIVE Vitamin D - Liver  In the liver, vitamin D is converted to  25-hydroxycholecalciferol Vitamin D ◦ 25(OH)D  25-Hydroxycholecalciferol is bound to an α-globulin in plasma and is the primary circulating form of Vitamin D INACTIVE Activation of Vitamin D - Kidney  In the renal cortex, 25-hydroxycholecalciferol undergoes hydroxylation by the enzyme 1 alpha hydroxlase at the C1 position to produce:  1,25-dihydroxycholecalciferol Physiologically Active  This reaction stimulated and tightly controlled by PTH Vitamin D Formation  In the skin, 7-dehydrocholesterol is converted by ultraviolet light to vitamin D3.  In the liver, vitamin D is converted to 25-hydroxycholecalciferol.  In the cortex of the kidney, 25hydroxycholecalciferol is converted to 1,25- dihydroxycholecalciferol in a reaction stimulated and tightly controlled by PTH. 1 alpha hydroxlase is stimulated by: Increase in PTH Decrease in free [Ca++] Decrease in [Phosphate] Vitamin D Formation & [Ca++]  Because PTH formation is stimulated by reduction in the blood concentration of calcium [Ca2+]  Formation of Vitamin D (1,25-dihydroxycholecalciferol) also increases when the calcium concentration in the blood decreases.  [Ca2+]  [PTH]  [ Vitamin D] Gastrointestinal Calcium Absorption In the epithelial cells of the small intestine  Role of Vitamin D _ Absorption of Ca2+  Ca2+ cannot cross the cell membrane of the epithelial cells without the mechanisms activated by 1,25-dihydroxycholecalciferol  Vitamin D stimulates formation of ◦ calcium binding protein ◦ calcium-stimulated ATPase ◦ alkaline phosphatase ◦ all of which promote absorption of calcium ions out of the lumen of the intestine. Regulation of Vitamin D Synthesis  Renal cells produce 1,25-dihydroxycholecalciferol (the active metabolite) or 24,25-dihydroxycholecalciferol (the inactive metabolite) depending on the “status” of Ca2+ in the body. Regulation of Vitamin D Synthesis  When Dietary Ca2+ is insufficient ◦ low dietary intake of Ca2+ and decreased plasma Ca2+ concentration, the active metabolite is preferentially synthesized to ensure that additional Ca2+ will be absorbed from the gastrointestinal tract  1α-hydroxylase enzyme ◦ The production of the active metabolite is regulated by changing the activity of the 1α-hydroxylase enzyme 1α-Hydroxylase activity  1α-Hydroxylase activity is increased by : ◦ Decreased plasma Ca2+ concentration ◦ Increased circulating levels of PTH ◦ Decreased plasma phosphate concentration Actions of Vitamin D  The overall role of vitamin D is to ◦ increase plasma levels of both Ca2+ and phosphate ◦ to promote mineralization of new bone  Vitamin D has coordinated actions on: ◦ Intestine - increases both Ca2+ and phosphate absorption ◦ Kidney - stimulates both Ca2+ and phosphate reabsorption ◦ Bone - stimulate osteoclast activity and bone resorption 1,25-dihydroxycholecalciferol Pathophysiology of Vitamin D  Rickets ◦ In children, vitamin D deficiency causes rickets, a condition in which insufficient amounts of Ca2+ and phosphate are available to mineralize the growing bones  Osteomalacia ◦ In adults, new bone fails to mineralize, resulting in bending and softening of the weight-bearing bones Bone Mass in Balance Bone Producing  Osteoblasts deposit new bone.  Weight bearing activities   Calcium / Vitamin D Estrogen / Testosterone Resorption / Bone Loss  Osteoclast cells digest bone  Inactivity  Deficient nutrition ◦ inadequate Ca++, vitamin D  Low Estrogen  Low Testostone Parathyroid Hormone (PTH) - Summary  Bone: promote bone resorption, delivering both Ca2+ and phosphate to ECF  Kidney: PTH has two actions on the kidney. (1) PTH inhibits phosphate reabsorption (phosphaturia); (2) PTH stimulates Ca2+ reabsorption.  Small Intestine: PTH does not have direct actions on the small intestine. PTH stimulates formation of vitamin D  Vit D stimulates intestinal Ca2+ absorption. Calcitonin Calcitonin  Secreted from the parafollicular cells (C cells) found in the thyroid gland.  Calcitonin secretion increases in response to elevation of the extracellular calcium concentration ◦ Calcitonin “tones down” [Ca++]  Calcitonin effects oppose those of PTH in the bone and renal tubule  the magnitude of its effects is much less than that of PTH. Parafollicular Cells (C cells) Calcitonin  The major stimulus for calcitonin secretion is increased plasma Ca2+ concentration  The major action of calcitonin is to  inhibit osteoclastic bone resorption  decreases the plasma Ca2+ concentration. Calcitonin  In contrast to PTH, calcitonin does not participate in the minute-to-minute regulation of the plasma [Ca2+]  The physiologic role for calcitonin in humans is uncertain ◦ thyroidectomy (with decreased calcitonin levels) ◦ thyroid tumors (with increased calcitonin levels)  Do NOT result in derangement of Ca2+ metabolism  as would be expected if calcitonin had important regulatory functions.