Download Hormone Control of Calcium Metabolism

Hormone Control of
Calcium Metabolism
ผศ.ดร.พญ.สุวัฒณี คุปติวฒ
ุ ิ
ภาควิชาสรีรวิทยา
คณะแพทยศาสตรศิริราชพยาบาล
Aims
„
„
Calcium Homeostasis
Hormone Control Calcium Metabolism
„
Vitamin D
PTH
Calcitonin
„
Other hormones
„
„
„
Calcium and Phosphate function
1
Calcium homeostasis
THE ONLY “IN”
BONE
DIETARY HABITS,
SUPPLEMENTS
BLOOD CALCIUM
INTESTINAL ABSORPTION
KIDNEYS
URINE
THE PRINCIPLE “OUT”
Bone release Ca++
Kidney conserve Ca++
Ca++ is excreted in urine
Bone incorporates Ca++
Intestine absorbs Ca++
Ca++ is excreted from diet
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Parathyroid hormone (PTH)
„
84-amino acids polypeptide hormone
PTH is released from the chief cells of
the parathyroid gland.
„ A decreased in plasma Ca2+mediates the
release of PTH through calcium sensing receptor
(CaSR).
„
„
PTH binds to PTH/PTHrP receptor.
„
2nd messenger of PTH is cAMP (PKA pathway).
Parathyroid glands
3
PTH actions (Kidney)
Direct
ƒ PTH increases Ca2+ reabsorption at the distal
convoluted tubules (transcellular).
„
PTH increases PO43 - and HCO3- excretion
in the urine.
„
PTH inhibit NPT2a at proximal tubule.
PTH action (distal tubules)
Ca2+
Paracellular (proximal tubule)
Ca2+
PTH
TrpV 5&6: epithelium calcium channels
NCX: sodium/calcium exchanger
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Proximal tubule
Pi
Pi
PTH R
NPT2a
PTH
NPT2a
Pi
PTH actions (Kidney)
Indirect
PTH
1-α hydroxylase
25 HCC
1,25 DHCC
Intestinal absorption of Ca2+
5
PTH actions (Bone)
PTH acts on osteoblasts to inhibit the
synthesis of collagen (inhibition of bone
formation).
„
ƒ PTH acts on osteoblasts to stimulate
secretion of RANKL , which acts on the
osteoclasts to promote demineralization
and Ca2+release (osteoclastic bone
resorption)
RANKL: receptor activator of NF-kB ligand
PTH actions (Bone)
„
„
PTH also activates Ca2+pumps within the
surface osteoblasts to move Ca2+out of bone
fluid and into the extracellular fluid (ECF).
[Ca2+] ×[PO43 - ] = คาคงที่
[Ca2+]
[PO43 - ]
[Ca2+]
[PO43 - ]
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Osteoblasts
RANKL
Osteoclast precursor cell
Osteoclast
PTH actions (Bone)
PTH (basal level)
Osteoblasts
Bone formation
Osteoclasts
Bone resorption
Bone remodeling
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PTH actions
Parathyroid glands
Decrease blood Ca++
Bone releases Ca++
Increase blood Ca++
Kidney conserve Ca++
Increase active Vit D
Intestine absorbs
Ca++
Abnormal PTH secretion
„
PTH deficit
„
„
„
parathyroidectomy
Hypocalcemia signs and symptoms
PTH excess
„
Primary hyperparathyroidism
is the most common cause of hypercalcemia.
The defect lies with the parathyroid tissue ex. adenoma
„
„
„
Secondary hyperparathyroidism
The defect is from other tissue such as chronic renal disease.
„
„
Hypercalcemia signs and symptoms
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Vitamin D synthesis
SKIN
LIVER
7-DEHYDROCHOLESTEROL
VITAMIN D3
KIDNEY
25(OH)VITAMIN D
25-HYDROXYLASE
1α-HYDROXYLASE
hν
VITAMIN D3
25(OH)VITAMIN D
(25-HCC)
1,25(OH)2 VITAMIN D
(1,25-DHCC)
(ACTIVE METABOLITE)
TISSUE-SPECIFIC VITAMIN D RESPONSES
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Vitamin D mechanism of action
The action of Vit. D is mediated by altered gene
transcription resulting in the synthesis of specific
proteins.
VIT D / VDR
RNA POL
Ex: CaBPs, Vitamin
D3receptor
5’ UNTRANSLATED REGION
VITAMIN D RESPONSIVE GENE
TRANSCRIPTION START SITE
IN THE NUCLEUS
Vitamin D action
ƒ GUT
ƒ
Ca2+ and PO4 3-absorption from the gut
epithelium
ƒ
Ca2+ binding protein (CaBP) or by affecting
2+
Ca transport directly
ƒ
plasma membrane Ca2+ ATPase pump Ca2+
(PMCA) from enterocyte to blood
ƒ BONE
ƒ
mineralization from blood Ca2+ to bone
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Vitamin D action (enterocyte)
Eletrochemical gradient
Ca2+
Ca2+
Ca2+
Ca2+
TrpV 5 & 6
Ca2+
Ca2+
Ca2+
Ca2+
IMCal: Intestinal membrane calcium binding protein
TrpV 5&6: epithelium calcium channels
Vitamin D action
ƒ KIDNEY
ƒ
tubular calcium reabsorption, possibly by
the action of CaBP
ƒ PARATHYROID
ƒ Inhibit transcription of the PTH gene
(feedback regulation)
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Abnormal Vitamin D secretion
„
Vitamin D deficit
„
„
Uncalcified osteoid tissue Clinical
syndromes broadly categorized as Rickets
and Osteomalacia.
Decreased blood calcium.
Vitamin D excess
„Hypercalcemia (rare).
„
Rickets / Osteomalacia
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Calcium, PTH, and Vitamin D
feedback loop
BONE RESORPTION
URINARY LOSS
SUPPRESS PTH
1,25(OH)2 D PRODUCTION
RISING BLOOD Ca2+
NORMAL BLOOD Ca2+
FALLING BLOOD Ca2+
BONE RESORPTION
URINARY LOSS
STIMULATE PTH
1,25(OH)2 D PRODUCTION
Calcitonin
„
32 amino acids peptide.
Calcitonin is released from parafollicular
(C or clear cells) of the thyroid gland.
„
„
Increased plasma Ca2+can stimulate
calcitonin release.
cAMP is the second messenger in the secretory
process.
„
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Parafollicular cells
Calcitonin action
„
The exact physiologic role of calcitonin is
uncertain.
BONE
„
„
the osteclastic activity.
KIDNEY
„
„
Ca2+excretion in urine.
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Calcium homeostasis
Calcitonin
Vit D
THE ONLY “IN”
BONE
DIETARY HABITS,
SUPPLEMENTS
PTH
BLOOD CALCIUM
INTESTINAL ABSORPTION
Calcitonin
Active vitamin D
PTH
KIDNEYS
Vit D
PTH
URINE
THE PRINCIPLE “OUT”
Other Hormones
„
GH, IGFs
„Activate chondrocytes
„
intestinal Ca2+absorption.
„
renal PO43 – reabsorption.
Thyroid hormone
„
„
Physiological level: Increase bone formation.
„
Excess: Increase bone resorption by
decrease1,25 DHCC and increase
renal Ca2+excretion.
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Sex hormones
Estrogen
PTH action on bone
Bone resorption
Androgen
PTH action on kidney
Ca2+ excretion
Bone formation
Sex hormones
Osteoporosis
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Other Hormones
„
Glucocorticoids
„
GI Ca2+absorption.
„
Renal Ca2+excretion.
„
PTH.
Osteoporosis
Blood Calcium Function
„
Structure of bone and teeth
„
Hormone secretion and hormone action
„
Neurotransmission
„
Muscle contraction
„
Blood Clotting
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Blood Phosphate Function
„
Structure of bone and teeth
„
A covalent modifier of the activity of numerous
enzymes.
„
A component of many intermediates in glucose
metabolism eg G-6-P.
„
A component of all high energy transfer
compounds eg ATP, NADP.
Blood Calcium
„
Blood calcium are tightly regulated at
approximately 10 mg/dl.
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Hypocalcemia: sign and
symptoms
„
NEUROMUSCULAR:
„
CNS: IRRITABILITY, SEIZURES
„
CARDIOVASCULAR: QT PROLONGATION
INVOLUNTARY
MUSCLE CONTRACTION (TETANY), 7TH CRANIAL
NERVE EXCITABILITY (CHVOSTEK’S SIGN),
NUMBNESS AND TINGLING IN FACE, HANDS,
AND FEET, TROUSSEAU’S SIGN
ON ECG
Hypercalcemia: sign and
symptoms
„
CNS: lethargy, depression, decreased alertness,
confusion, and coma
„
„
GI: anorexia, constipation, nausea, and vomiting
RENAL: diuresis, impaired concentrating ability,
dehydration. Hypercalciuria is a risk for kidney
stones.
„
SKELETAL: most causes of hypercalcemia are
associated with increased bone resorption, and thus,
fracture risk
„
CARDIOVASCULAR: shortened QT interval
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Integrated regulation of
calcium and phosphate
Plasma calcium
PTH secretion
Plasma Phosphate
Renal Phosphate
1,25 DHCC
INTESTINAL ABSORPTION
BONE RESORPTION
Urine
calcium
Plasma
calcium
Plasma
phosphate
Urine
phosphate
Calcitonin secretion
20
Trousseau’s sign
Chvostek’s sign
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Ca2+
CaSR
PTH
PTH
Gq +Gi
-
pro-PTH
Down stream
signaling pathway
PTH gene
prepro-PTH
PTH mRNA
Ca2+
Nucleus
1,251,25-Vit D
CaSR
PTH
PTH
Gq +Gi
-
pro-PTH
Down stream
signaling pathway
prepro-PTH
PTH mRNA
- +
PTH gene
CaSR gene
Nucleus
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