Regulation of Calcium Homeostasis

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Regulation of Calcium Homeostasis

• The Importance of Calcium
• Intake, Storage, and Excretion of Calcium
• Calcitonin
• Parathyroid Hormone
• Vitamin D
• Other Factors Influencing Bone and Calcium
  Metabolism

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Why is Calcium Important?

• Calcium is involved in signal transduction

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Role of Calcium in Hormone Secretion

• Secretion of peptide hormones is often dependent
  upon influx of calcium into the cell.
• - Influx of calcium results in cell
  depolarization.
• - Calcium can act as a second messenger in
  cells, via calmodulin to cause secretion
• -Calcium may influence microtubule contraction.

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Role of Calcium in Bone Formation

• Adequate calcium supply is required for bone
  formation, as calcium and phosphate are the
  minerals which make up bone.
• Bone is mineralized by the precipitation of
  calcium and phosphate in a basic environment.
• Without calcium, have decreased bone
  mineralization and strength.

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Role of Calcium in Muscular Contraction

• Increased free cytoplasmic calcium binds with
  troponin to cause muscle contraction.

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Role of Calcium in Neuronal Excitation

• Changes in extracellular calcium concentrations
  influence the resting membrane potential of
  cells.
• Abnormally low calcium levels result in increased
  permeability of neuronal membranes to sodium,
  resulting in hyperexcitability of neurons.

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Role of Calcium in Blood Clotting

• Calcium is required for proper functioning of
  clotting factors.
• Thus, regulation of calcium levels is critical
  for the function of many systems!

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Intake, Storage and Excretion of Calcium

• Calcium is the most abundant mineral in the body.
• The amount of calcium in the body is a balance
  between intake, storage, and excretion.
• This balance is controlled by transfer of calcium
  between three organs intestine, bone, and kidney.

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Intake of Calcium

• About 1000 mg of calcium 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....)

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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.

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Excretion of Calcium

• The major site of calcium excretion in the body
  is the kidneys.
• The rate of calcium loss and reabsorption at the
  kidney can be regulated.
• Regulation of absorption, storage, and excretion
  of calcium results in maintenance of calcium
  homeostasis.

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Endocrine Factors Regulating Calcium Homeostasis

• There are three main hormones which regulate
  calcium balance
• calcitonin
• parathyroid hormone
• vitamin D
• In addition, other factors influence bone and
  calcium metabolism.

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Role of Calcitonin in Calcium Homeostasis

• Calcitonin is produced from the parafollicular
  cells of the thyroid gland (also called clear
  cells).
• It is composed of 32 amino acids, derived from a
  prohormone.

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Actions of Calcitonin

• The major action of calcitonin is on bone
  metabolism.
• Calcitonin inhibits activity of osteoclasts,
  resulting in decreased bone resorption (and
  decreased plasma calcium levels).

osteoclasts destroy bone to release calcium
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Minor Actions of Calcitonin

• Calcitonin may also have minor effects on the
  kidney
• - increased calcium excretion
• - increased H secretion/K retention
• - increased production of active form of vitamin
  D

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Mechanism of Action of Calcitonin

• Calcitonin acts through a Gs receptor, increasing
  cyclic AMP (main point).
• However, the calcitonin receptor can be coupled
  to Gi (inhibit cyclic AMP) and Go (stimulating
  PKC) this mechanism is used in the kidney to
  stimulate H secretion/K retention.

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Regulation of Calcitonin Release

• Calcitonin release is stimulated by increased
  circulating plasma calcium levels.
• Calcitonin release is also caused by the
  gastrointestinal hormones gastrin and
  cholecystokinin (CCK), whose levels increase
  during digestion of food.

food (w/ calcium?)
gastrin, CCK
increased calcitonin
decreased bone resorption
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What is the Role of Calcitonin in Humans?

• Removal of the thyroid gland has no effect on
  plasma calcium levels!
• Excessive calcitonin release does not affect bone
  metabolism!
• Other mechanisms are more important in regulating
  calcium metabolism (ie, PTH and vitamin D).

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Calcitonin Gene-Related Peptide(CGRP)

• The calcitonin gene produces several products due
  to alternative splicing of the RNA.
• CGRP is an alternative product of the calcitonin
  gene.
• CGRP does NOT bind to the calcitonin receptor.
• CGRP is expressed in thyroid, heart, lungs, GI
  tract, and nervous tissue.
• It is believed to function as a neurotransmitter,
  not as a regulator of calcium.

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Parathyroid Hormone

• Parathyroid hormone (PTH) is produced by the four
  parathyroid glands, on the posterior aspect of
  the thyroid gland.

• PTH is composed of 84 amino acids, formed from a
  prohormone.
• It is THE MAJOR regulator of calcium homeostasis
  in humans.

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Actions 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 D

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Actions 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

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Mechanism of Action of PTH

• PTH binds to a G protein-coupled receptor.
• Binding of PTH to its receptor activates TWO
  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

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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).

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Calcium Receptor, cAMP, and PTH Release
Ca
decreased cAMP
decreased PTH release
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Calcium Receptor, cAMP, and PTH Release
increased cAMP
increased PTH release
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PTH-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?

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The Role of Vitamin D in Calcium Homeostasis

• The active metabolite of vitamin D is required
  for efficient absorption of calcium in the small
  intestine (major effect).
• In addition, vitamin D may have a minor effect on
  bone resorption (and is required for the effects
  of PTH on bone).

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Sources and Metabolism of Vitamin D

• The production of the active metabolite of
  vitamin D requires the actions of three major
  organ systems, the skin, liver, and kidney.
• Vitamin D3 (cholecalciferol) is produced in the
  skin upon exposure to the sun. It is also found
  in milk and other foods.
• Cholecalciferol then is hydroxylated in the
  liver, to form 25-hydroxycholecalciferol.
• 25-hydroxycholecalciferol is then 1-hydroxylated
  in the kidney to form the active metabolite,
  1,25-dihydroxycholecalciferol (calcitriol).

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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).

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Regulation of Vitamin D by PTH and Phosphate
Levels
PTH
1-hydroxylase
25-hydroxycholecalciferol
1,25-dihydroxycholecalciferol
increase phosphate resorption
Low phosphate
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Mechanism of Action of Vitamin D

• Vitamin D interacts with an intracellular
  receptor which acts as a transcription factor,
  binding to the 5flanking region of target genes.
• Lag period of several hours before effects are
  observed, consistent with a transcriptional
  effect.
• One target gene identified calcium transport
  protein in the intestine and in bone.
• Rapid, nongenomic effects on calcium channels may
  also take place.

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Other Factors Influencing Bone and Calcium
Metabolism

• Estrogens Androgens both stimulate bone
  formation during childhood and puberty.
• Estrogen inhibits PTH-stimulated bone resorption.
• Estrogen increases calcitonin levels
• Osteoblasts have estrogen receptors, respond to
  estrogen with bone growth.
• Postmenopausal women (low estrogen) have an
  increased incidence of osteoporosis and bone
  fractures.

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Findings of NIH Consensus Panel on Osteoporosis

• The National Institutes of Health has concluded
  the following
• Adequate calcium and vitamin D intake are crucial
  to develop optimal peak bone mass and to preserve
  bone mass throughout life.
• Factors contributing to low calcium intakes are
  restriction of dairy products, a generally low
  level of fruit and vegetable consumption, and a
  high intake of low calcium beverages such as
  sodas.

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Influences of Growth Hormone

• Normal GH levels are required for skeletal
  growth.
• GH increases intestinal calcium absorption and
  renal phosphate resorption.
• Insufficient GH prevents normal bone production.
• Excessive GH results in bone abnormalities
  (acceleration of bone formation AND resorption).

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Effects of Glucocorticoids

• Normal levels of glucocorticoids (cortisol) are
  necessary for skeletal growth.
• Excess glucocorticoid levels decrease renal
  calcium reabsorption, interfere with intestinal
  calcium absorption, and stimulate PTH secretion.
• High glucocorticoid levels also interfere with
  growth hormone production and action, and gonadal
  steroid production.
• Net Result rapid osteoporosis (bone loss).

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Influence of Thyroid Hormones

• Thyroid hormones are important in skeletal growth
  during infancy and childhood (direct effects on
  osteoblasts).
• Hypothyroidism leads to decreased bone growth.
• Hyperthyroidism can lead to increased bone loss,
  suppression of PTH, decreased vitamin D
  metabolism, decreased calcium absorption. Leads
  to osteoporosis.

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Effects of Diet

• Increasing dietary intake of calcium may prevent
  osteoporosis in postmenopausal women.
• Excessive sodium intake in diet can impair renal
  calcium reabsorption, resulting in lower blood
  calcium and increased PTH release. Normally, PTH
  results in increased absorption of calcium from
  the GI tract (via vitamin D). But in aging
  women, vitamin D production decreases, so calcium
  isnt absorbed, and PTH instead causes increased
  bone loss.
• High protein diet may cause loss of calcium from
  bone, due to acidic environment resulting from
  protein metabolism and decreased reabsorption at
  the kidney.

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Effects of Exercise

• Bone cells respond to pressure gradients in
  laying down bone.

• Lack of weight-bearing exercise decreases bone
  formation, while increased exercise helps form
  bone.

• Increased bone resorption during immobilization
  may
• result in hypercalcemia

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Next Lecture.
Growth Hormones