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Regulation of Calcium Homeostasis

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Bone is mineralized by the precipitation of calcium and phosphate in a basic environment. Without calcium, have decreased bone mineralization and strength. ... – PowerPoint PPT presentation

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Title: Regulation of Calcium Homeostasis


1
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

2
Why is Calcium Important?
  • Calcium is involved in signal transduction

3
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.

4
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.

5
Role of Calcium in Muscular Contraction
  • Increased free cytoplasmic calcium binds with
    troponin to cause muscle contraction.

6
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.

7
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!

8
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.

9
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....)

10
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.

11
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.

12
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.

13
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.

14
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
15
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

16
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.

17
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
18
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).

19
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.

20
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.

21
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23
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

24
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

25
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26
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

27
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).

28
Calcium Receptor, cAMP, and PTH Release
Ca
decreased cAMP
decreased PTH release
29
Calcium Receptor, cAMP, and PTH Release
increased cAMP
increased PTH release
30
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?

31
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).

32
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).

33
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).

34
Regulation of Vitamin D by PTH and Phosphate
Levels
PTH
1-hydroxylase
25-hydroxycholecalciferol
1,25-dihydroxycholecalciferol
increase phosphate resorption
Low phosphate
35
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.

36
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.

37
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.

38
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).

39
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).

40
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.

41
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.

42
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

43
Next Lecture.
Growth Hormones
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