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Hormone Control of Calcium Metabolism

ผศ.ดร.พญ.สุวัฒณี คุปติวฒิุ

ภาควิชาสรีรวิทยา

คณะแพทยศาสตรศิริราชพยาบาล

Aims

Calcium HomeostasisHormone Control Calcium Metabolism

Vitamin DPTHCalcitoninOther hormones

Calcium and Phosphate function

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Calcium homeostasis

INTESTINAL ABSORPTION

DIETARY HABITS,

SUPPLEMENTS BLOOD CALCIUM

BONE

KIDNEYS

URINE

THE ONLY “IN”

THE PRINCIPLE “OUT”

Bone release Ca++Bone release Ca++ Bone incorporates Ca++Bone incorporates Ca++

Intestine absorbs Ca++Intestine absorbs Ca++Kidney conserve Ca++Kidney conserve Ca++

Ca++ is excreted in urineCa++ is excreted in urine Ca++ is excreted from dietCa++ is excreted from diet

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Parathyroid hormone (PTH)84-amino acids polypeptide hormonePTH 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 glandsParathyroid glands

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PTH actions (Kidney)Direct

PTH increases PO43 - and HCO3- excretion

in the urine.

PTH inhibit NPT2a at proximal tubule.

PTH increases Ca2+ reabsorption at the distal

convoluted tubules (transcellular).

PTH action (distal tubules)

PTH

TrpV 5&6: epithelium calcium channels

NCX: sodium/calcium exchanger

Paracellular (proximal tubule)CaCa2+2+CaCa2+2+

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Proximal tubule

NPT2aNPT2a

PTHPTH

PTH RPTH RPiPi

PiPi

PiPi

NPT2aNPT2a

Indirect

PTH actions (Kidney)

25 HCC 1,25 DHCC1-α hydroxylase

PTH

Intestinal absorption of Ca2+

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PTH acts on osteoblasts to inhibit the synthesis of collagen (inhibition of bone formation).

PTH actions (Bone)

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 also activates Ca2+pumps within the surface osteoblasts to move Ca2+out of bone fluid and into the extracellular fluid (ECF).

PTH actions (Bone)

[Ca2+] ×[PO43 - ] = คาคงที่คาคงที่

[Ca2+] [PO43 - ]

[Ca2+] [PO43 - ]

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Osteoblasts

Osteoclast precursor cell RANKL

Osteoclast

PTH actions (Bone)PTH (basal level)

Osteoblasts

Bone formation

Osteoclasts

Bone resorption

Bone remodeling

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PTH actionsPTH actionsDecrease blood Ca++Decrease blood Ca++

Parathyroid glandsParathyroid glands

Increase blood Ca++Increase blood Ca++

Bone releases Ca++Bone releases Ca++ Kidney conserve Ca++Kidney conserve Ca++ Increase active Increase active VitVit D D Intestine absorbs Intestine absorbs

Ca++Ca++

Abnormal PTH secretion

PTH deficit parathyroidectomyHypocalcemia signs and symptoms

PTH excess Primary hyperparathyroidism

is the most common cause of hypercalcemia.The defect lies with the parathyroid tissue ex. adenoma

Secondary hyperparathyroidismThe defect is from other tissue such as chronic renal disease.

Hypercalcemia signs and symptoms

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Vitamin D synthesis

SKIN LIVER KIDNEY

7-DEHYDROCHOLESTEROL

VITAMIN D3

VITAMIN D3

25(OH)VITAMIN D

(25-HCC)

hν25-HYDROXYLASE

25(OH)VITAMIN D

1,25(OH)2 VITAMIN D

(1,25-DHCC)

(ACTIVE METABOLITE)

1α-HYDROXYLASE

TISSUE-SPECIFIC VITAMIN D RESPONSES

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Vitamin D mechanism of actionThe action of Vit. D is mediated by altered gene

transcription resulting in the synthesis of specific proteins.

5’ UNTRANSLATED REGION VITAMIN D RESPONSIVE GENE

TRANSCRIPTION START SITE

VIT D / VDR

RNA POL

IN THE NUCLEUS

Ex: CaBPs, Vitamin D3receptor

Vitamin D actionGUT

Ca2+ and PO4 3-absorption from the gut

epithelium

Ca2+ binding protein (CaBP) or by affecting Ca2+ transport directly

plasma membrane Ca2+ ATPase pump Ca2+

(PMCA) from enterocyte to blood

BONEmineralization from blood Ca2+ to bone

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Vitamin D action (enterocyte)

IMCal: Intestinal membrane calcium binding protein

Eletrochemical gradient

TrpV 5 & 6

TrpV 5&6: epithelium calcium channels

Ca2+

Ca2+

Ca2+Ca2+

Ca2+

Ca2+

Ca2+

Ca2+

Vitamin D action

KIDNEY

tubular calcium reabsorption, possibly by the action of CaBP

PARATHYROID

Inhibit transcription of the PTH gene (feedback regulation)

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Abnormal Vitamin D secretionVitamin D deficit

Uncalcified osteoid tissue Clinical syndromes broadly categorized as Ricketsand Osteomalacia.Decreased blood calcium.

Vitamin D excessHypercalcemia (rare).

Rickets / Osteomalacia

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Calcium, PTH, and Vitamin D feedback loop

NORMAL BLOOD Ca2+

RISING BLOOD Ca2+

FALLING BLOOD Ca2+

SUPPRESS PTH

STIMULATE PTH

BONE RESORPTION

URINARY LOSS

1,25(OH)2 D PRODUCTION

BONE RESORPTION

URINARY LOSS

1,25(OH)2 D PRODUCTION

Calcitonin32 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.

BONEthe osteclastic activity.

KIDNEY

Ca2+excretion in urine.

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Calcium homeostasis

INTESTINAL ABSORPTION

DIETARY HABITS,

SUPPLEMENTS BLOOD CALCIUM

BONE

KIDNEYS

URINE

THE ONLY “IN”

THE PRINCIPLE “OUT”

Active vitamin DPTH

Vit DPTHCalcitonin

CalcitoninVit D

PTH

Other HormonesGH, IGFs

Thyroid hormone

Activate chondrocytesintestinal Ca2+absorption.renal PO4

3 – reabsorption.

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 Androgen

PTH action on bone PTH action on kidney

Bone resorption Ca2+ excretion

Bone formation

Sex hormones Osteoporosis

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Other HormonesGlucocorticoids

Osteoporosis

GI Ca2+absorption.Renal Ca2+excretion.

PTH.

Blood Calcium FunctionStructure 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 glucosemetabolism 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: INVOLUNTARY MUSCLE CONTRACTION (TETANY), 7TH CRANIAL NERVE EXCITABILITY (CHVOSTEK’S SIGN), NUMBNESS AND TINGLING IN FACE, HANDS, AND FEET, TROUSSEAU’S SIGN

CNS: IRRITABILITY, SEIZURES

CARDIOVASCULAR: QT PROLONGATION ON ECG

Hypercalcemia: sign and symptoms

CNS: lethargy, depression, decreased alertness, confusion, and comaGI: anorexia, constipation, nausea, and vomitingRENAL: 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 riskCARDIOVASCULAR: 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

Plasma phosphate

Urine phosphate

Urine calcium

Plasmacalcium

Calcitonin secretion

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Trousseau’s sign

Chvostek’s sign

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CaSRCaSR

CaCa2+2+

PTH gene

Gq +Gi

Down stream signaling pathway

--

PTH mRNA

prepro-PTH

pro-PTH

PTH

PTH

--

NucleusNucleus

CaSRCaSRCaCa2+2+

PTH gene

Gq +Gi

Down stream signaling pathway

--

PTH mRNA

prepro-PTH

pro-PTH

PTH

PTH

--

NucleusNucleus

1,251,25--Vit DVit D

--

CaSR gene++