Calcium Homeostasis: Parathyroid Hormone, Calcitonin and Vitamin D3

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Calcium Homeostasis: Parathyroid Hormone, Calcitonin and Vitamin D3. Physiological Importance of Calcium. Ca salts in bone provide structural integrity of the skeleton. Ca is the most abundant mineral in the body. The amount of Ca is balance among intake, storage, and excretion.
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Calcium Homeostasis: Parathyroid Hormone, Calcitonin and Vitamin D3Physiological Importance of Calcium
  • Ca salts in bone provide structural integrity of the skeleton.
  • Ca is the most abundant mineral in the body.
  • The amount of Ca is balance among intake, storage, and excretion.
  • This balance is controlled by transfer of Ca among 3 organs: intestine, bone, kidneys.
  • Ca ions in extracellular and cellular fluids is essential to normal function of a host of biochemical processes
  • Neuoromuscular excitability and signal transduction
  • Blood coagulation
  • Hormonal secretion
  • Enzymatic regulation
  • Neuron excitation
  • Intake of Calcium
  • About 1000 mg of Ca is ingested per day.
  • About 200 mg of this is absorbed into the body.
  • Absorption occurs in the small intestine, and requires vitamin D (stay tuned....)
  • Storage of Calcium
  • The primary site of storage is our bones (about 1000 grams).
  • Some calcium is stored within cells (endoplasmic reticulum and mitochondria).
  • Bone is produced by osteoblast cells which produce collagen, which is then mineralized by calcium and phosphate (hydroxyapatite).
  • Bone is remineralized (broken down) by osteoclasts, which secrete acid, causing the release of calcium and phosphate into the bloodstream.
  • There is constant exchange of calcium between bone and blood.
  • Excretion of Calcium
  • The major site of Ca excretion in the body is the kidneys.
  • The rate of Ca loss and reabsorption at the kidney can be regulated.
  • Regulation of absorption, storage, and excretion of Ca results in maintenance of calcium homeostasis.
  • Regulation of [Calcium]
  • The important role that calcium plays in so many processes dictates that its concentration, both extracellularly and intracellularly, be maintained within a very narrow range.
  • This is achieved by an elaborate system of controls
  • Regulation of Intracellular [Calcium]
  • Control of cellular Ca homeostasis is as carefully maintained as in extracellular fluids
  • [Ca2+]cyt is approximately 1/1000th of extracellular concentration
  • Stored in mitochondria and ER
  • “pump-leak” transport systems control [Ca2+]cyt
  • Calcium leaks into cytosolic compartment and is actively pumped into storage sites in organelles to shift it away from cytosolic pools.
  • Extracellular Calcium
  • When extracellular calcium falls below normal, the nervous system becomes progressively more excitable because of increase permeability of neuronal membranes to sodium.
  • Hyperexcitability causes tetanic contractions
  • Hypercalcemic tetany [Ca2+]cyt
  • Extracellular Calcium
  • Three definable fractions of calcium in serum:
  • Ionized calcium 50%
  • Protein-bound calcium 40%
  • 90% bound to albumin
  • Remainder bound to globulins
  • Calcium complexed to serum constituents 10%
  • Citrate and phosphate
  • Extracellular Calcium
  • Binding of calcium to albumin is pH dependent
  • Acute alkalosis increases calcium binding to protein and decreases ionized calcium
  • Patients who develop acute respiratory alkalosis have increased neural excitability and are prone to seizures due to low ionized calcium in the extracellular fluid which results in increased permeability to sodium ions
  • Calcium and Phosphorous
  • Ca is tightly regulated with P in the body.
  • P is an essential mineral necessary for ATP, cAMP 2nd messenger systems, and other roles
  • Calcium TurnoverCalcium in Blood and Bone
  • Ca2+ normally ranges from 8.5-10 mg/dL in the plasma.
  • The active free ionized Ca2+ is only about 48% 46% is bound to protein in a non-diffusible state while 6% is complexed to salt.
  • Only free, ionized Ca2+ is biologically active.
  • Phosphate TurnoverPhosphorous in Blood and Bone
  • PO4 normal plasma concentration is 3.0-4.5 mg/dL. 87% is diffusible, with 35% complexed to different ions and 52% ionized.
  • 13% is in a non-diffusible protein bound state. 85-90% is found in bone.
  • The rest is in ATP, cAMP, and proteins
  • Calcium and Bone
  • 99% of Ca is found in the bone. Most is found in hydroxyapatite crystals. Very little Ca2+ can be released from the bone– though it is the major reservoir of Ca2+ in the body.
  • Structure of BonesHaversian canals within lamellaeCalcium Turnover in Bones
  • 80% of bone is mass consists of cortical bone– for example: dense concentric layers of appendicular skeleton (long bones)
  • 20% of bone mass consists of trabecular bone– bridges of bone spicules of the axial skeleton (skull, ribs, vertebrae, pelvis)
  • Trabecular bone has 5 X greater surface area, though comprises lesser mass.
  • Because of greater accessibility trabecular bone is more important to calcium turnover
  • Bones
  • 99% of the Calcium in our bodies is found in our bones which serve as a reservoir for Ca2+ storage.
  • 10% of total adult bone mass turns over each year during remodeling process
  • During growth rate of bone formation exceeds resporption and skeletal mass increases.
  • Linear growth occurs at epiphyseal plates.
  • Increase in width occurs at periosteum
  • Once adult bone mass is achieved equal rates of formation and resorption maintain bone mass until age of about 30 years when rate of resportion begins to exceed formation and bone mass slowly decreases.
  • Types of Bone Cells
  • There are 3 major types of bone cells: Osteoblasts are the differentiated bone forming cells and secrete bone matrix on which Ca2+ and PO43- precipitate.
  • Osteocytes, the mature bone cells are enclosed in bone matrix.
  • Osteoclasts is a large multinucleated cell derived from monocytes whose function is to resorb bone. Inorganic bone is composed of hydroxyapatite and organic matrix is composed primarily of collagen.
  • Bone Formation
  • Active osteoblasts synthesize and extrude collagen
  • Collagen fibrils form arrays of an organic matrix called the osetoid.
  • Calcium phosphate is deposited in the osteoid and becomes mineralized
  • Mineralization is combination of CaPO4, OH-, and H3CO3– hydroxyapatite.
  • Mineralization
  • Requires adequate Calcium and phosphate
  • Dependent on Vitamin D
  • Alkaline phosphatase and osteocalcin play roles in bone formation
  • Their plasma levels are indicators of osteoblast activity.
  • Canaliculi
  • Within each bone unit is a minute fluid-containing channel called the canaliculi.
  • Canaliculi traverse the mineralized bone.
  • Interior osteocytes remain connected to surface cells via syncytial cell processes.
  • This process permits transfer of calcium from enormous surface area of the interior to extracellular fluid.
  • Bones cellsControl of Bone Formation and Resorption
  • Bone resorption of Ca2+ by two mechanims: osteocytic osteolysis is a rapid and transient effect and osteoclasitc resorption which is slow and sustained.
  • Both are stimulated by PTH. CaPO4 precipitates out of solution id its solubility is exceeded. The solubility is defined by the equilibrium equation: Ksp = [Ca2+]3[PO43-]2.
  • In the absence of hormonal regulation plasma Ca2+ is maintained at 6-7 mg/dL by this equilibrium.
  • Osteocytic Osteolysis
  • Transfer of calcium from canaliculi to extracellular fluid via activity of osteocytes.
  • Does not decrease bone mass.
  • Removes calcium from most recently formed crystals
  • Happens quickly.
  • Bone Resorption
  • Does not merely extract calcium, it destroys entire matrix of bone and diminishes bone mass.
  • Cell responsible for resorption is the osteoclast.
  • Bone Remodeling
  • Endocrine signals to resting osteoblasts generate paracrine signals to osteoclasts and precursors.
  • Osteoclasts resorb and area of mineralized bone.
  • Local macrophages clean up debris.
  • Process reverses when osteoblasts and precursors are recruited to site and generate new matrix.
  • New matrix is minearilzed.
  • New bone replaces previously resorbed bone.
  • Osteoclasts and Ca2+ ResorptionCalcium, Bones and Osteoporosis
  • The total bone mass of humans peaks at 25-35 years of age.
  • Men have more bone mass than women.
  • A gradual decline occurs in both genders with aging, but women undergo an accelerated loss of bone due to increased resorption during perimenopause.
  • Bone resorption exceeds formation.
  • Calcium, Bones and Osteoporosis
  • Reduced bone density and mass: osteoporosis
  • Susceptibility to fracture.
  • Earlier in life for women than men but eventually both genders succumb.
  • Reduced risk:
  • Calcium in the diet
  • habitual exercise
  • avoidance of smoking and alcohol intake
  • avoid drinking carbonated soft drinks
  • Vertebrae of 40- vs. 92-year-old women Note the marked loss of trabeculae with preservation of cortex.Hormonal Control of BonesHormonal Control of Ca2+
  • Three principal hormones regulate Ca2+ and three organs that function in Ca2+ homeostasis.
  • Parathyroid hormone (PTH), 1,25-dihydroxy Vitamin D3 (Vitamin D3), and Calcitonin, regulate Ca2+ resorption, reabsorption, absorption and excretion from the bone, kidney and intestine. In addition, many other hormones effect bone formation and resorption.
  • Vitamin D
  • Vitamin D, after its activation to the hormone 1,25-dihydroxy Vitamin D3 is a principal regulator of Ca2+.
  • Vitamin D increases Ca2+ absorption from the intestine and Ca2+ resorption from the bone .
  • Synthesis of Vitamin D
  • Humans acquire vitamin D from two sources.
  • Vitamin D is produced in the skin by ultraviolet radiation and ingested in the diet.
  • Vitamin D is not a classic hormone because it is not produce and secreted by an endocrine “gland.” Nor is it a true “vitamin” since it can be synthesized de novo.
  • Vitamin D is a true hormone that acts on distant target cells to evoke responses after binding to high affinity receptors
  • Synthesis of Vitamin D
  • Vitamin D3 synthesis occurs in keratinocytes in the skin.
  • 7-dehydrocholesterol is photoconverted to previtamin D3, then spontaneously converts to vitamin D3.
  • Previtamin D3 will become degraded by over exposure to UV light and thus is not overproduced.
  • Also 1,25-dihydroxy-D (the end product of vitamin D synthesis) feeds back to inhibit its production.
  • Synthesis of Vitamin D
  • PTH stimulates vitamin D synthesis. In the winter or if exposure to sunlight is limited (indoor jobs!), then dietary vitamin D is essential.
  • Vitamin D itself is inactive, it requires modification to the active metabolite, 1,25-dihydroxy-D.
  • The first hydroxylation reaction takes place in the liver yielding 25-hydroxy D.
  • Then 25-hydroxy D is transported to the kidney where the second hydroxylation reaction takes place.
  • Synthesis of Vitamin D
  • The mitochondrial P450 enzyme 1a-hydroxylase converts it to 1,25-dihydroxy-D, the most potent metabolite of Vitamin D.
  • The 1a-hydroxylase enzyme is the point of regulation of D synthesis.
  • Feedback regulation by 1,25-dihydroxy D inhibits this enzyme.
  • PTH stimulates 1a-hydroxylase and increases 1,25-dihydroxy D.
  • Synthesis of Vitamin D
  • 25-OH-D3 is also hydroxylated in the 24 position which inactivates it.
  • If excess 1,25-(OH)2-D is produced, it can also by 24-hydroxylated to remove it.
  • Phosphate inhibits 1a-hydroxylase and decreased levels of PO4 stimulate 1a-hydroxylase activity
  • Regulation of Vitamin D Metabolism
  • PTH increases 1-hydroxylase activity, increasing production of active form.
  • This increases calcium absorption from the intestines, increases calcium release from bone, and decreases loss of calcium through the kidney.
  • As a result, PTH secretion decreases, decreasing 1-hydroxylase activity (negative feedback).
  • Low phosphate concentrations also increase 1-hydroxylase activity (vitamin D increases phosphate reabsorption from the urine).
  • Regulation of Vitamin D by PTH and Phosphate LevelsPTH1-hydroxylase25-hydroxycholecalciferol1,25-dihydroxycholecalciferolincrease phosphate resorptionLow phosphateSynthesis of Vitamin DVitamin D
  • Vitamin D is a lipid soluble hormone that binds to a typical nuclear receptor, analogous to steroid hormones.
  • Because it is lipid soluble, it travels in the blood bound to hydroxylated a-globulin.
  • There are many target genes for Vitamin D.
  • Vitamin D action
  • The main action of 1,25-(OH)2-D is to stimulate absorption of Ca2+ from the intestine.
  • 1,25-(OH)2-D induces the production of calcium binding proteins which sequester Ca2+, buffer high Ca2+ concentrations that arise during initial absorption and allow Ca2+ to be absorbed against a high Ca2+ gradient
  • Vitamin D promotes intestinal calcium absorption
  • Vitamin D acts via steroid hormone like receptor to increase transcriptional and translational activity
  • One gene product is calcium-binding protein (CaBP)
  • CaBP facilitates calcium uptake by intestinal cells
  • Clinical correlate
  • Vitamin D-dependent rickets type II
  • Mutation in 1,25-(OH)2-D receptor
  • Disorder characterized by impaired intestinal calcium absorption
  • Results in rickets or osteomalacia despite increased levels of 1,25-(OH)2-D in circulation
  • Vitamin D Actions on Bones
  • Another important target for 1,25-(OH)2-D is the bone.
  • Osteoblasts, but not osteoclasts have vitamin D receptors.
  • 1,25-(OH)2-D acts on osteoblasts which produce a paracrine signal that activates osteoclasts to resorb Ca++ from the bone matrix.
  • 1,25-(OH)2-D also stimulates osteocytic osteolysis.
  • Vitamin D and Bones
  • Proper bone formation is stimulated by 1,25-(OH)2-D.
  • In its absence, excess osteoid accumulates from lack of 1,25-(OH)2-D repression of osteoblastic collagen synthesis.
  • Inadequate supply of vitamin D results in rickets, a disease of bone deformation
  • Parathyroid Hormone
  • PTH is synthesized and secreted by the parathyroid gland which lie posterior to the thyroid glands.
  • The blood supply to the parathyroid glands is from the thyroid arteries.
  • The Chief Cells in the parathyroid gland are the principal site of PTH synthesis.
  • It is THE MAJOR of Ca homeostasis in humans.
  • Parathyroid GlandsSynthesis of PTH
  • PTH is translated as a pre-prohormone.
  • Cleavage of leader and pro-sequences yield a biologically active peptide of 84 aa.
  • Cleavage of C-terminal end yields a biologically inactive peptide.
  • Regulation of PTH
  • The dominant regulator of PTH is plasma Ca2+.
  • Secretion of PTH is inversely related to [Ca2+].
  • Maximum secretion of PTH occurs at plasma Ca2+ below 3.5 mg/dL.
  • At Ca2+ above 5.5 mg/dL, PTH secretion is maximally inhibited.
  • Calcium regulates PTHRegulation of PTH
  • PTH secretion responds to small alterations in plasma Ca2+ within seconds.
  • A unique calcium receptor within the parathyroid cell plasma membrane senses changes in the extracellular fluid concentration of Ca2+.
  • This is a typical G-protein coupled receptor that activates phospholipase C and inhibits adenylate cyclase—result is increase in intracellular Ca2+ via generation of inositol phosphates and decrease in cAMP which prevents exocytosis of PTH from secretory granules.
  • Regulation of PTH
  • When Ca2+ falls, cAMP rises and PTH is secreted.
  • 1,25-(OH)2-D inhibits PTH gene expression, providing another level of feedback control of PTH.
  • Despite close connection between Ca2+ and PO4, no direct control of PTH is exerted by phosphate levels.
  • Calcium regulates PTH secretionPTH action
  • The overall action of PTH is to increase plasma Ca2+ levels and decrease plasma phosphate levels.
  • PTH acts directly on the bones to stimulate Ca2+ resorption and kidney to stimulate Ca2+ reabsorption in the distal tubule of the kidney and to inhibit reabosorptioin of phosphate (thereby stimulating its excretion).
  • PTH also acts indirectly on intestine by stimulating 1,25-(OH)2-D synthesis.
  • Calcium vs. PTHActions of PTH: Bone
  • PTH acts to increase degradation of bone (release of calcium).
  • - causes osteoblasts to release cytokines, which stimulate osteoclast activity - stimulates bone stem cells to develop into osteoclasts - net result: increased release of calcium from bone - effects on bone are dependent upon presence of vitamin DActions of PTH: Kidney
  • PTH acts on the kidney to increase the reabsorption of calcium (decreased excretion).
  • Also get increased excretion of phosphate (other component of bone mineralization), and decreased excretion of hydrogen ions (more acidic environment favors dimineralization of bone)
  • ALSO, get increased production of the active metabolite of vitamin D3 (required for calcium absorption from the small intestine, bone demineralization).
  • NET RESULT: increased plasma calcium levels
  • Mechanism of Action of PTH
  • PTH binds to a G protein-coupled receptor.
  • Binding of PTH to its receptor activates 2 signaling pathways:
  • - increased cyclic AMP - increased phospholipase C
  • Activation of PKA appears to be sufficient to decrease bone mineralization
  • Both PKA and PKC activity appear to be required for increased resorption of calcium by the kidneys
  • Regulation of PTH Secretion
  • PTH is released in response to changes in plasma calcium levels.
  • - Low calcium results in high PTH release. - High calcium results in low PTH release.
  • PTH cells contain a receptor for calcium, coupled to a G protein.
  • Result of calcium binding: increased phospholipase C, decreased cyclic AMP.
  • Low calcium results in higher cAMP, PTH release.
  • Also, vitamin D inhibits PTH release (negative feedback).
  • Calcium Receptor, cAMP, and PTH ReleaseCa++decreased cAMPdecreased PTH releaseCalcium Receptor, cAMP, and PTH Releaseincreased cAMPincreased PTH releasePTH-Related Peptide
  • Has high degree of homology to PTH, but is not from the same gene.
  • Can activate the PTH receptor.
  • In certain cancer patients with high PTH-related peptide levels, this peptide causes hypercalcemia.
  • But, its normal physiological role is not clear.
  • - mammary gland development/lactation? - kidney glomerular function? - growth and development?Primary Hyperparathyroidism
  • Calcium homeostatic loss due to excessive PTH secretion
  • Due to excess PTH secreted from adenomatous or hyperplastic parathyroid tissue
  • Hypercalcemia results from combined effects of PTH-induced bone resorption, intestinal calcium absorption and renal tubular reabsorption
  • Pathophysiology related to both PTH excess and concomitant excessive production of 1,25-(OH)2-D.
  • Hypercalcemia of Malignancy
  • Underlying cause is generally excessive bone resorption by one of three mechanisms
  • 1,25-(OH)2-D synthesis by lymphomas
  • Local osteolytic hypercalcemia
  • 20% of all hypercalcemia of malignancy
  • Humoral hypercalcemia of malignancy
  • Over-expression of PTH-related protein (PTHrP)
  • PTHrP
  • Three forms of PTHrP identified, all about twice the size of native PTH
  • Marked structural homology with PTH
  • PTHrP and PTH bind to the same receptor
  • PTHrP reproduce full spectrum of PTH activities
  • PTH receptor defect
  • Rare disease known as Jansen’s metaphyseal chondrodysplasia
  • Characterized by hypercalcemia, hypophosphotemia, short-limbed dwarfism
  • Due to activating mutation of PTH receptor
  • Rescue of PTH receptor knock-out with targeted expression of “Jansen’s transgene”
  • Hypoparathyroidism
  • Hypocalcemia occ
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