Transcript Document

Calcium,
Parathyroid Hormone,
and Vitamin D
Ahmed Ziada PGY4
August 21st, 2013
Objectives:
•
Calcium Homeostasis and hormonal regulation of calcium
homeostasis
• Identify the origin, target organs and cell types, and physiologic
effects of parathyroid hormone
• Regulation of parathyroid hormone secretion and the role of the
calcium-sensing receptor
• Identify the sources of vitamin D and describe the biosynthetic
pathway involved in modifying it to its biologically active form
• Identify the target organs and cellular mechanisms of action of
vitamin D.
Calcium Homeostasis
Background
• Calcium is the fifth most abundant element and is the most
prevalent cation in the human body
•
Approximately 1-1.3 kg of calcium can be found in a healthy adult,
99% of which is in the form of hydroxyapatite in the skeleton; the
remaining 1% is contained in the ECF
• Calcium is essential for bone mineralization, neuromuscular
function, and secretion of hormones and enzymes
• Because Ca is not made in the body, a diet that contains Ca is
essential to maintain normal serum Ca ( yogurt, cheese, eggs, milk,
spinach, fish, okra, broccoli, almonds, sesame seeds, and peas)
Calcium Homeostasis
• Serum (plasma) calcium exists in 3 distinct forms
Calcium Concentrations in Body Fluids
Total serum calcium
2.1-2.6 mmol/L
Ionized calcium
1.1-1.3 mmol/L
Protein-bound calcium
0.9-1.1 mmol/L
Complexed calcium
Intracellular free calcium
0.18 mmol/L
0.00018 mmol/L (180 nmol/L)
Calcium Homeostasis
• The resting intracellular (cytosolic) calcium concentration is
approximately 100 nM, but this can increase to 1 mM by the
release of Ca2+ from intracellular stores or by uptake of
extracellular Ca2+ in response to cellular activation
• The extracellular ionized calcium concentration is
approximately 10,000-fold higher than the intracellular
calcium concentration and remains virtually constant at
approximately 1 mM
Calcium Homeostasis
Control of Calcium Homeostasis
• The extracellular fluid (or plasma) calcium concentration is tightly
controlled by a complex homeostatic mechanism involving fluxes of
calcium between the ECF and the kidney, bone, and gut
•
These fluxes are carefully regulated by three major hormones:
parathyroid hormone (PTH), calcitonin, and 1,25-dihydroxyvitamin D
[1,25(OH)2D3]
• Important cellular functions are dependent on the maintenance of the
extracellular calcium concentration within a narrow range
•
Disturbances of this tightly regulated homeostatic system leads to
disorders of calcium metabolism that have predictable effects, which can
be ascribed to effect on these cellular functions
Calcium Homeostasis
• An average Western diet provides a
calcium intake of ∼1 g of elemental
calcium per day
• Typically, ∼30% (300 mg) is absorbed, the
majority across the small intestine and a
small percentage in the colon
• Because gut secretion of calcium is
relatively constant at 125 mg per day, the
net calcium absorption is ∼175 mg per day
for a healthy adult in normal calcium
balance
•
Calcium absorbed from the gut enters the
blood and is filtered by the kidney.The
majority of filtered calcium (>98%) is
reabsorbed ; thus, only 175 mg per
day is excreted in healthy individuals
Interaction of Bone, Kidney and Intestine in
Maintaining Calcium Homeostasis
Calcium Homeostasis
Hormonal Effects on Calcium Homeostasis
• Blood ionized calcium concentrations are remarkably stable in
healthy individuals because of the homeostatic system
involving the actions of the three calciotropic hormones on
the target organs of bone, gut, and kidney, and possibly also
on fluxes between the bone canalicular fluid and the ECF
•
Normal calcium homeostasis is primarily dependent on the
interactions of PTH, 1,25(OH)2D3, and calcitonin on these
organs to maintain the ionized calcium concentration within a
very narrow range
Calcium Homeostasis
• The challenge of the cellular calcium is to maintain a cytosolic
[Ca2+] of about 100 nmol/L, about 10,000-fold less than what is
present outside cells (~1.0 mmol/L), providing for rapid fluxes
through the intracellular compartment as required for regulation
while maintaining a large gradient across the cell membrane
• The calcium gradient across the cell membrane is maintained by
ATP-dependent calcium pumps, Na+-Ca2+ exchangers, and the
storage of calcium within intracellular sites
Calcium Homeostasis
• Calcium can enter cells through several types of calcium
channels, some of which are voltage operated or receptor
operated, to provide for rapid influx in response to
depolarization or receptor stimulation
• The cell also maintains large stores of calcium in microsomal
and mitochondrial pools
Hormonal Effects on Calcium Homeostasis
Schematic diagram of calcium homeostasis
Parathyroid
Hormon
Anatomy of the Parathyroid Glands
• PTH is secreted from four glands located adjacent to the thyroid
gland in the neck
• The glands weigh an average of 40 mg each. The two superior
glands are usually found near the posterior aspect of the thyroid
capsule
•
the inferior glands are most often located near the inferior
thyroid margin
•
However, the exact location of the glands is variable, and 12% to
15% of normal persons have a fifth parathyroid gland
PTH
• PTH is produced almost exclusively by the parathyroid glands
• PTH is an 84-amino acid peptide that is synthesized by the chief
cells of the parathyroid gland
• Secretion of PTH is highly dependent on the ionized calcium
concentration and represents a simple negative feedback loop
•
The serum PTH concentration decreases as the serum Ca
concentration increases, although PTH secretion is not entirely
suppressible
•
There is a relatively narrow range of regulation of PTH secretion
by extracellular calcium, with little further effect when total
corrected serum calcium is >2.9 mmol/L or <2.1 mmol/L
The relationship between the serum-ionized calcium level and the
simultaneous serum concentration of intact PTH in normal
humans
•
Serum calcium concentration
was altered by the infusion
of calcium (closed circles) or
citrate (closed triangles)
•
Parathyroid sensitivity to
changes in serum calcium is
maximal within the normal
range (the shaded area). Low
concentrations of PTH persist
in the face of hypercalcemia.
Hormonal Effects on Calcium Homeostasis
Biological Actions of PTH
1.
Stimulation of osteoclastic
bone resorption and
release of calcium and
phosphate from bone
2.
Stimulation of calcium
reabsorption and inhibition
of phosphate reabsorption
from the renal tubules
3.
Stimulation of renal
production of 1,25(OH)2D3,
which increases intestinal
absorption of calcium and
phosphate
Parathyroid Ca2+ Receptor
• The Ca2+ sensor is a G protein –coupled receptor located on the plasma
membrane of the parathyroid chief cells; it is also found in kidney tubule cells
and thyroid C cells
Parathyroid Ca2+-sensing receptor and regulation of (PTH) release
Additional Factors that Regulate Parathyroid
Hormone Release
• Elevations in plasma phosphate levels increase PTH
secretion by:
Decreasing phospholipase A2 activity and arachidonic
acid formation, thus removing the inhibitory effect
on PTH secretion
 Elevations in phosphate levels can also affect PTH
release indirectly by decreasing plasma Ca2+ levels
and vitamin D activation
• In contrast, hypophosphatemia markedly decreases
PTH mRNA and plasma PTH
Additional Factors that Regulate Parathyroid
Hormone Release
•
Mg2+ concentrations also regulate PTH secretion in a similar
manner to that of calcium
• PTH release can be stimulated by a moderate decrease in plasma
Mg2+. However, very low serum concentrations of Mg2+ induce a
paradoxical block in PTH release. The mechanism for this effect has
been suggested to be the result of activation of the -subunits of
the calcium-sensing receptor G-proteins, mimicking the activation
of the receptor and thus inhibiting PTH secretion
Additional Factors that Regulate Parathyroid
Hormone Release
• This combined decrease in Mg2+ and Ca2+ leads to impairment in
the individual's ability to secrete PTH
•
Moreover, severe hypomagnesemia impairs not only the release
of PTH from the parathyroid gland in response to hypocalcemia,
but it also prevents the responsiveness of bone to PTH-mediated
bone resorption
•
Adrenergic agonists have been shown to increase PTH release
through -adrenergic receptors on parathyroid cells
Cellular Effects of Parathyroid Hormone
In bone
• PTH releases calcium from stores that are readily available and
in equilibrium with the extracellular fluid (ECF)
• Subsequently, PTH stimulates release of calcium (and also
phosphate) by activation of bone resorption
• PTH binds to receptors found in osteoblasts resulting in a
cascade of events culminating in osteoclast activation and
leading to a rapid release of Ca2+ from the bone matrix into the
extracellular compartment, where it enters the systemic
circulation
Cellular Effects of Parathyroid Hormone
• PTH-mediated effects in bone involve osteoblast activation and
stimulation of genes vital to the processes of:
1.
2.
3.
4.
degradation of the extracellular matrix and bone remodeling
production of growth factors (insulin-like growth factor 1)
Stimulation and recruitment of osteoclasts
PTH also increases the number of osteoblasts, by decreasing
their apoptosis and increasing their proliferation
• Although chronic elevations of PTH result in bone resorption,
intermittent administration of PTH stimulates bone formation
more than bone resorption
Cellular Effects of Parathyroid Hormone
 In the kidney
• PTH directly stimulates Ca2+ reabsorption, phosphate excretion,
and the activity of 1-hydroxylase
• The site of PTH regulation of Ca2+ reabsorption is the distal
tubules
•
Ca2+ reabsorption by the proximal tubules occurs primarily
through a paracellular pathway that is not regulated by
hormones or drugs
Cellular Effects of Parathyroid Hormone
• In the distal tubule, Ca2+ absorption is entirely transcellular
and is regulated by PTH, vitamin D, and calcitonin; it can also
be affected by Ca2+-sparing drugs such as thiazide diuretics
• PTH decreases the renal (and intestinal) reabsorption of
phosphate by decreasing the expression of the type II
Na+/PO42– cotransporter
PTHrP
• When secreted in abundance by malignant tumors, PTHrP
produces severe hypercalcemia by activating the PTH-1 receptor
• The physiologic roles of PTHrP are quite different from those of
PTH. PTHrP is produced in many fetal and adult tissues
• PTHrP is required for normal development as a regulator of the
proliferation and mineralization of chondrocytes and as a regulator
of placental calcium transport.
• In postnatal life, PTHrP also appears to regulate epithelialmesenchymal interactions that are critical for development of the
mammary gland, skin, and hair follicle
•
In most physiologic circumstances, PTHrP carries out local rather
than systemic actions
Calcitonin
Calcitonin
• Calcitonin is a 32–amino acid peptide hormone derived from
procalcitonin, produced by cells of neural crest origin
(parafollicular or C cells) in the thyroid gland
• The secretion of CT is under the control of the ionized [Ca2+]
• The C cell uses the same CaSR as the parathyroid cell to sense
changes in the ambient ionized [Ca2+]
•
In contrast to parathyroid cells, C cells increase secretion of CT
in response to hypercalcemia and shut off hormone secretion
during hypocalcemia
Calcitonin
• Elevations in plasma Ca2+ higher than 9 mg/dL ( 2.25 mmol\L)
stimulate the release of calcitonin
•
Calcitonin has a half-life of approximately 5 minutes and is
metabolized and cleared by the kidney and the liver
•
The release of calcitonin is also stimulated by gastrin, a
gastrointestinal hormone
Cellular Effects of Calcitonin
• The main physiologic function of calcitonin is to decrease
plasma Ca2+ and phosphate concentrations, mainly by
decreasing bone resorption
•
The 2 target organs for calcitonin's physiologic effects are
bone and kidney
• Calcitonin inhibits bone resorption, predominantly by
inhibition of osteoclast motility and differentiation
Cellular Effects of Calcitonin
• In the kidney, calcitonin increases urinary Ca2+ excretion by
inhibition of renal tubular calcium reabsorption
• The mechanism involved is through opening of low affinity
Ca2+ channels in the luminal membrane and the stimulation
of the Na+/Ca2+ exchanger in the basolateral membrane,
both actions depending on the activation of adenylate
cyclase.
• In hypercalcemic patients with metastatic bone disease,
the administration of calcitonin induces a rapid decrease in
plasma calcium primarily through inhibition of renal tubular
reabsorption
Additional Regulators of Ca2+ and Bone
Metabolism
Regulator
Action
PTH
Increases bone resorption and plasma Ca2
Vitamin D
Increases intestinal Ca2+ absorption, bone resorption
Calcitonin
Decreases bone resorption and plasma Ca2+
Sex steroids (androgens
and estrogens)
Growth hormone and
insulinlike growth factor
Thyroid hormone
Increase 1-hydroxylase activity, Increase osteoprotegerin
synthesis Net decrease in bone loss
Stimulate bone synthesis and growth
Prolactin
Increases renal Ca2+ reabsorption and 1-hydroxylase activity
Glucocorticoids
Increase bone resorption, decrease bone synthesis
Inflammatory cytokines
Increase bone resorption
Increases bone resorption
VITAMIN
D
Vitamin D
• Vitamin D is a lipid-soluble vitamin
• Synthesized from plant-derived precursors or through the
action of sunlight from cholesterol-derived precursors found
in the skin or obtained from dietary intake of fortified milk,
fatty fish, cod-liver oil, and, to a lesser extent, eggs
•
Active vitamin D (calcitriol) is the product of 2 consecutive
hydroxylation steps, (first in the liver and then in the kidney)
Cutaneous Synthesis of Vitamin D
• Vitamin D3 is formed in the skin from 7-dehydrocholesterol,
which is distributed throughout the epidermis and dermis
• Vitamin D3 is carried in the bloodstream primarily bound to
vitamin D–binding protein (DBP), an -globulin produced in the
liver
• DBP has a lower affinity for vitamin D3 than other vitamin D
metabolites. Therefore, vitamin D3 could be selectively
removed from skin by the gradient established by selective
binding to DBP
Cutaneous Synthesis of Vitamin D
• Because the deepest levels of the epidermis make the most
vitamin D3 when the skin is irradiated, the distance over which
vitamin D3 must diffuse to reach the circulation is short
Vitamin D metabolism and physiologic
effects at target organs
Dietary Sources and Intestinal Absorption
• Ultraviolet light may not be sufficient to maintain adequate
production of vit.D in the skin
• The farther away from the equator one lives, the shorter the
period of the year during which the intensity of sunlight is
sufficient to produce vitamin D3
• Most milk products in the United States are supplemented
with vitamin D
• Although plants and mushrooms contain ergosterol, their
content of vitamin D2 is limited unless they are irradiated with
ultraviolet light during processing
Dietary Sources and Intestinal Absorption
• Moderate to high concentrations in fish oils and fish liver and
in lesser concentrations in eggs
• Vitamin D is absorbed from the diet in the small intestine with
the help of bile salts. The presence of fat in the lumen
decreases vitamin D absorption
• Little vitamin D is stored in the liver. Excess vitamin D is stored
in adipose tissue and muscle
Mechanisms of Action
• The main function of vitamin D metabolites is the regulation of
calcium and phosphate homeostasis, which occurs in
conjunction with PTH. The gut, kidney, and bone are the
principal target tissues
• 1,25(OH)2D is the most biologically active, if not the only vitamin
D metabolite involved in maintaining calcium and phosphate
homeostasis.
Intestinal Calcium Transport
The primary function of calcitriol
or 1,25 (OH)2D3 in the intestine
is increased absorption of
calcium and phosphorous.
Vitamin D is carried into the
nucleus of the enterocyte, where
it binds to receptor proteins and
acts as a steroid hormone,
resulting in the stimulation and
synthesis of new messenger RNA
molecules.
These messenger RNA molecules
are then translated to produce a
protein, Calbindin, a calcium
binding protein in the intestinal
mucosa that is synthesized in
response to the action of calcitriol
(active vit. D). This calcium
binding protein is needed for Ca
transport across the cell
membranes
Actions of Vitamin D in Bone
• the best established action of 1,25(OH)2D is to stimulate bone
resorption. This is accompanied by an increase in osteoclast
number and activity and decreased collagen synthesis
• The increase in osteoclast number and activity is now known
to be mediated by the production in osteoblasts of a
membrane-bound protein called receptor activator of NFkappa B ligand (RANKL), which acts on its receptor (RANK) in
osteoclasts and their precursors to stimulate osteoclast
differentiation and activity
•
1,25(OH)2D is one of several hormones (PTH and selected
cytokines are others) that stimulate RANKL production
Actions of Vitamin D in Bone
• 1,25(OH)2D and PTH stimulation
of the mobilization of calcium
from the skeleton through
interactions with their respective
receptors on osteoblasts, which
induce expression of the receptor
activator of nuclear factor-B
(RANK) ligand (RANKL)
•
The receptor activator of nuclear
factor-B on immature osteoclasts
binds to the receptor activator of
nuclear factor-B ligand, which
causes the cells to mature and
coalesce with other osteoclast
precursors to become mature
multinuclear osteoclasts
Actions of Vitamin D in Kidney
• The kidney expresses VDRs, and 1,25(OH)2D stimulates the
expression of calbindin, TRPV5 (the renal homolog of the
intestinal TRPV6), and Ca2+-ATPase (PMCA) in the distal tubule
as well as 24,25(OH)2D production in the proximal tubule
• However, the role of 1,25(OH)2D in regulating calcium and
phosphate transport across the renal epithelium remains
controversial
Actions of Vitamin D in Kidney
•
25(OH)D may be more important than 1,25(OH)2D in acutely
stimulating calcium and phosphate reabsorption by the
kidney tubules
• In vivo studies are complicated by the effect of 1,25(OH)2D on
other hormones, particularly PTH, which appears to be more
important than the vitamin D metabolites in regulating
calcium and phosphate handling by the kidney
Actions of Vitamin D in Other Tissues
• The responses of these tissues to 1,25(OH)2D are as varied as the
tissues themselves
• 1,25(OH)2D regulates hormone production and secretion, including
stimulation of insulin secretion from the pancreas and prolactin
from the pituitary
• Inhibiting PTH secretion from the parathyroid gland, renin secretion
from the kidney, and atrial naturetic peptides from the heart
1,25(OH)2D enables the innate immune system by inducing
antimicrobial peptides such as cathelidicin
• Myocardial contractility and vascular tone are modulated by
1,25(OH)2D
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