PTH: Ca / Vit D metabolites / other factors,...

Page 1

Ca regulating hormones

• Introduction: effects of Ca / PO4 ions; Parathyroid: anatomy, histology, PTH; Thyroid: anatomy, histology, Calcitonin; Kidney: Vit D. Overview of Ca regulation: bone, kidney, and GI tract as effectors of Ca regulating hormones.

• PTH: structure, receptor, secretion, effect of Ca / Vit D metabolites / other factors, effects

• Calcitonin: structure, biological actions, effect on osteoclasts and bone reabsorption

• Vit D: production and metabolism, absorption, transport and excretion, biological actions

• Diseases: hypoPTH, low Ca tetany, hyperPTH, kidney stones, rickets, osteoporosis. Case study (e.g. hypocalciuric hypercalcemia)

06

Introduction

Hormones and “story lines”

thyroid

gland

blood

Ca PTH

Calcitonin

Vit.D

+ +

-

+

kidney

parathyroid

gland

Page 2

Ca Regulating Hormones

• Introduction

• Parathyroid

• Thyroid

• Vitamin D

• Bone turnover

• Pathologies

Why do blood Ca and PO4 levels are

regulated ???

• Ca is required for Na permeability in nerves, Ach release at NMJ, excitation - contraction coupling in muscles, (e.g.. low ECF-Ca and tetany)

• Ca serves as intracellular signal for some hormones (e.g.. Epinephrine on stroke volume)

• Ca is needed for some enzymes’ effect, for the secretion of proteins, for blood clotting to occur (e.g.. EDTA)

• Ca is a constituent of bone (Ca storage depot)

• PO4 functions as part of intracellular buffer systems

• PO4 is an important constituent of macromolecules such as nucleic acids, phospholipids, metabolic intermediates, and phosphoproteins

• PO4 is a constituent of bone (PO4 storage depot)


• Introduction

• Parathyroid

• Thyroid

• Vitamin D

• Bone turnover

• Pathologies

Why do blood Ca and PO4 levels are

regulated ???

excitable non-excitable

VGNaC G

q

Tyr-K Gs Gi

VmCa

VGCC

SERCa

ecfCa entry

icf

IP3 Ry

storage

mito metab

packagingexocytosis

gene express..

cytoskeleton

enzymes/R

PKC

PLC

PLD

IP3RRyR

VGCC

TTX - sensitive

TTX - non sensitive

• VGCCs, LVA vs HVA

• LVA, rapid and voltage inactivation

• HVA, slow inactivation

• T-,L-,N-,P-,Q, and R-type of VGCCs

• diversity due to multiple genes for Ca channel subunits and alternative splicing. The alpha1 subunit has the voltage sensor, gating machinery, and a channel pore.

• basal pacemaker activity, plasma membrane Ca oscillator, action potentials last longer (50-500 ms)

• some NPs, Nts and hormones act by modulating spontaneous activity of the pituitary membrane oscillator

Ca serves as intracellular signal

Page 3

• Introduction

• Parathyroid

• Thyroid

• Vitamin D

• Bone turnover

• Pathologies

What endocrine signals control all these

calcium fluxes ???


• Introduction

• Parathyroid

• Thyroid

• Vitamin D

• Bone turnover

• Pathologies

What endocrine signals control all these

calcium fluxes ???


blood

Ca bone

kidney

intestine

resorption

formation

reabsorptionfiltration

secretion

absorptionPTH and Vit.D

increase bloodCa

while

Calcitonin

decreases it

PTH

Calcitonin

PTH

Calcitonin

Vit. D

calcium receptor

parathyroid gland

PTH

PTH receptorGs / AC

Gq / PLC

bone resorption, osteoclast

kidney, Ca reabsorption, Vit. D

intestine, Ca absorption

Calcitonin

thyroid gland

calcium

receptor

Calcitonin

receptor

Gs / AC

bone formation, osteoblast

kidney, Ca filtration

intestine, Ca secretion

blood Ca

decrease

blood Caincreas

e

Page 4

• Introduction

• Parathyroid

• Thyroid

• Vitamin D

• Bone turnover

• Pathologies


The Ca receptor is a 7 tm domain

receptor with its large amino

terminal domain in the extra

cellular side of the plasma

membrane

Potential glycosylation sites are

located in the extracellular domain

Potential PKC phosphorylation

sites are in the intracellular

domain

Hypercalcemia decreases cAMP

and PTH release from parathyroid,

while hypocalcemia increases

both cAMP and PTH release

Teophylline and cAMP stimulate

PTH release

Examples of pathologies: pseudo

hypoparathyroidism type Ia (alpha

subunit of Gs) and familial hypo-

calciuria hypercalcemia (Ca

receptor)

The Ca sensor is a seven transmembrane

domain receptor

ECF

ICF

• Introduction

• Parathyroid

• Thyroid

• Vitamin D

• Bone turnover

• Pathologies

PTH is only made in the parathyroid gland

and is essential for Ca homeostasis


Page 5

• Introduction

• Parathyroid

• Thyroid

• Vitamin D

• Bone turnover

• Pathologies




• PTH is made in the para-thyroid only (84 aa). It is essential for Ca homeostasis

• PTH acts directly on the skeleton and kidneys

• PTH is the product of a single copy gene (pre-pro-PTH)

• PTH gene is subject to strong repressor activity in all cells but parathyroids

• PTH gene transcription is negatively regulated by ECF- Ca and by active Vit. D

• cis elements in PTH gene include Ca response element (CaRE), Vit. D response element (VDRE), and a cAMP response element (CRE)

• Introduction

• Parathyroid

• Thyroid

• Vitamin D

• Bone turnover

• Pathologies




PTH on Ca absorption

in distal nephron

PTH on Ca absorption

on proximal tubule

Page 6

• Introduction

• Parathyroid

• Thyroid

• Vitamin D

• Bone turnover

• Pathologies


• PTH is made in the para-thyroid only (84 aa). It is essential for Ca homeostasis

• PTH acts directly on the skeleton and kidneys

• PTH is the product of a single copy gene (pre-pro-PTH)

• PTH gene is subject to strong repressor activity in all cells but parathyroids

• PTH gene transcription is negatively regulated by ECF- Ca and by active Vit. D

• cis elements in PTH gene include Ca response element (CaRE), Vit. D response element (VDRE), and a cAMP response element (CRE)

R

PTHAC

PLC

ATP

cAMP, PKA

PI2

IP3, Ca rise

DAG, PKC

Gs

Gq



• Introduction

• Parathyroid

• Thyroid

• Vitamin D

• Bone turnover

• Pathologies

PTH secretion and plasma calcium

concentration


PTH

increases

plasma Ca concentration

As Ca plasma

content rises

PTH secretion decreases

Page 7

• Introduction

• Parathyroid

• Thyroid

• Vitamin D

• Bone turnover

• Pathologies

PTH stimulates osteoclasic activity

and Calcitonin inhibits it


• Introduction

• Parathyroid

• Thyroid

• Vitamin D

• Bone turnover

• Pathologies




Page 8

• Introduction

• Parathyroid

• Thyroid

• Vitamin D

• Bone turnover

• Pathologies




• Introduction

• Parathyroid

• Thyroid

• Vitamin D

• Bone turnover

• Pathologies




A) Local osteolytic hypercalcemia

secondary to leukemia

B) Hypercalcemia of malignancy

2nd to squamous cell

carcinoma

C) Hyperparathyroidism. Note the

abundant osteoclasts (large

arrows), osteoblasts (small

arrows) and osteoids

Page 9

• Introduction

• Parathyroid

• Thyroid

• Vitamin D

• Bone turnover

• Pathologies




A hand

radiograph in

primary hyper-parathyroidism.

Note the sub-

periosteal

erosions, which

are more prominents

along the radial

border of the

phalanges.

• Introduction

• Parathyroid

• Thyroid

• Vitamin D

• Bone turnover

• Pathologies

The mechanism of action elicited by PTH

involves AC and PLC


Page 10

• Introduction

• Parathyroid

• Thyroid

• Vitamin D

• Bone turnover

• Pathologies

The mechanism of action elicited by PTH

involves AC and PLC


• Introduction

• Parathyroid

• Thyroid

• Vitamin D

• Bone turnover

• Pathologies

Overall regulation of calcium balance by

PTH


Page 11

• Introduction

• Parathyroid

• Thyroid

• Vitamin D

• Bone turnover

• Pathologies

The mechanism of action elicited by

calcitonin involves AC and cAMP


• Calcitonin is synthesized (32 aa peptide) by parafollicular or C cells of the thyroid gland

• its primary action is to inhibit bone resorption by inhibiting osteoclast lysosomal activity

• its gene encodes multiple mRNA (CGRP) whose peptides ( and ß) cause arterial vasodilatation. CGRP is widely distributed in central & peripheral nervous system, heart, lungs, thyroid, & GI

• the main stimuli for Calcitonin secretion are an elevated serum Ca and the GI hormone gastrin

• its mechanism of action is through cAMP / PKA

Calcitonin

• Introduction

• Parathyroid

• Thyroid

• Vitamin D

• Bone turnover

• Pathologies









Calcitonin

Page 12

• Introduction

• Parathyroid

• Thyroid

• Vitamin D

• Bone turnover

• Pathologies









• Introduction

• Parathyroid

• Thyroid

• Vitamin D

• Bone turnover

• Pathologies









R

ACATP

cAMPGs

CO2 + H2O <---><---> H2CO3 <--->

<---> H + HCO3

HCO3

Cl + H -> HCl

-

+ -

-

carbonic anhydrase

+

HCO3-

-Cl

lysosomalenzymes

calcified bone

-

osteoclast

ruffledborder

Calcitonin

pump

lysosome

Page 13

• Introduction

• Parathyroid

• Thyroid

• Vitamin D

• Bone turnover

• Pathologies

Calcitonin and CGRP, two different ways of

processing the same gene


• Introduction

• Parathyroid

• Thyroid

• Vitamin D

• Bone turnover

• Pathologies

Vit.D is activated in the kidney by the

action of PTH


• produced in kidney, acts on the intestine, bone, kidney, and the parathyroid gland (VDR, DNA)

• acts as steroids do in nuclei of target cells. Its main effect is to increase GI - Ca absorption

• inhibits PTH synthesis and secretion. Use in secondary hyperPTH of chronic renal failure

• liver 25-hydroxylation is an obligatory step for binding to the Vit. D receptor (VDR). Highest activity occurs after kidney 1 -hydroxylation

• regulatory control is at a switching mechanism in kidney between 1 and 25 hydroxylase. Inputs are low PTH, Ca, PO4, and other hormones

irradiation

7-Dehydro

cholesterol

(pro Vit. D)

Cholecalci-

ferol

(Vit.

D3)

25-Hydroxy

cholecalciferol

(25 - (OH) - D3)

1, 25 -

Dihydroxy

cholecalci-

ferol

( 1, 25 -

(OH)2

D3 )

24, 25 - Dihydroxy

cholecalciferol

( 24, 25 - (OH)2 D3 )

25 -

hydroxy-

lation1 -

hydroxy

- latio

n

24 -

hydroxy-

lation

kidney

liver

skin

-

PTH

Low PO4

Low Ca

Estrogen

Prolactin

GH

Placental

lactogen

+

Page 14

• Introduction

• Parathyroid

• Thyroid

• Vitamin D

• Bone turnover

• Pathologies


action of PTH


• produced in kidney, acts on the intestine, bone, kidney, and the parathyroid gland (VDR, DNA)

• acts as steroids do in nuclei of target cells. Its main effect is to increase GI - Ca absorption

• inhibits PTH synthesis and secretion. Use in secondary hyperPTH of chronic renal failure

• liver 25-hydroxylation is an obligatory step for binding to the Vit. D receptor (VDR). Highest activity occurs after kidney 1 -hydroxylation

• regulatory control is at a switching mechanism in kidney between 1 and 25 hydroxylase. Inputs are low PTH, Ca, PO4, and other hormones

7-dehydro-

cholesterol

cholecalciferol

(inactive Vit D3)

25-hydroxy-

cholecalciferol

(inactive Vit D3)

1-25-hydroxy-

cholecalciferol

(active Vit D3) 24-25-(OH)2-D3

skin

liver

kidney

• Introduction

• Parathyroid

• Thyroid

• Vitamin D

• Bone turnover

• Pathologies


action of PTH


Page 15

• Introduction

• Parathyroid

• Thyroid

• Vitamin D

• Bone turnover

• Pathologies

Vit.D activation is inhibited in the kidney by

PO4 and in the parathyroid by Ca on PTH


• Introduction

• Parathyroid

• Thyroid

• Vitamin D

• Bone turnover

• Pathologies

The mechanism of action of Vit.D is at the

genomic level


(antagonistic effect of glucocorticoids at a genomic level)

Page 16

• Introduction

• Parathyroid

• Thyroid

• Vitamin D

• Bone turnover

• Pathologies


genomic level


• Introduction

• Parathyroid

• Thyroid

• Vitamin D

• Bone turnover

• Pathologies


• In its “free” state VDR receptor binds to its HRE as a heterodimer with retinoid-X. The carboxy-terminus of VDR interacts with TFIIB preventing the formation of a stable preinitiation complex and, together with a co-repressor, silences transcription.

• Upon Vit. D binding, its receptor undergoes a conformational change, dissociation of the co-repressor, a decreased interaction of the VDR with the carboxy-terminus TFIIB and an increase interaction of the VDR amino-terminus with TFIIB.

• These changes facilitate TFIIB binding an assembly of a stable preinitiation complex, the binding of RNA polymerase II and the activation of transcription initiation.

• Antagonistic effect of glucocorticoids at a genomic level


genomic level

Page 17

• Introduction

• Parathyroid

• Thyroid

• Vitamin D

• Bone turnover

• Pathologies



genomic level

• Introduction

• Parathyroid

• Thyroid

• Vitamin D

• Bone turnover

• Pathologies


Radiographic appearance of osteoporosis

in humans

Right

hip Lumbar

spine

osteoporosis osteoporosis

Page 18

• Introduction

• Parathyroid

• Thyroid

• Vitamin D

• Bone turnover

• Pathologies



in humans

Adolescence

Young adults

After third decade

Menopause

Advance age

• Introduction

• Parathyroid

• Thyroid

• Vitamin D

• Bone turnover

• Pathologies



in humans

The vertebra show decreased

bone mineral density and

some vertebra are clearly

compressed.

Page 19

• Introduction

• Parathyroid

• Thyroid

• Vitamin D

• Bone turnover

• Pathologies


A model for the general control of bone

turnover

• Introduction

• Parathyroid

• Thyroid

• Vitamin D

• Bone turnover

• Pathologies


Examples of calcium - related endocrine

pathologies

• hyperPTH, primary or secondary, leads to altered function of bone cells, renal tubules, and GI mucosa (kidney stones, bone decalcification, bone fractures)

• secondary hyperPTH occurs associated with low Ca due to chronic renal disease or to Vit. D deficiency

• hypoPTH due to inactivating mutations of the PTH gene, and due to activating mutations in the parathyroid Ca-sensing receptor have been reported

• Vit.D-dependent rickets: type I is due to an inherited defect in the renal 1a-hydroxylase gene and the type II (rare) is due to an inherited defect in the VDR leading to grossly elevated serum 1, 25 - (OH)2 VD3

Page 20

• Introduction

• Parathyroid

• Thyroid

• Vitamin D

• Bone turnover

• Pathologies



pathologies

Osteomalacia (rickets)

caused by simple

nutritional Vit. D deficiency resulting from

impaired mineralization of

newly formed bone.

Osteomalacia is the result of a

lack of Vit. D, impairment of Vit. D metabolism, or

lack of Ca or P at the

mineralizing site.

Before growth plate closure

the same condition is referred as rickets and is characterized

by failure of calcification of

cartilage at the growth plate.

• Introduction

• Parathyroid

• Thyroid

• Vitamin D

• Bone turnover

• Pathologies



pathologies

Osteomalacia (rickets)

caused by hypophos-

phatemia. is also known as“phosphate diabetes”

or Vit. D resistant

rickets. Is associated

with growth retardation

and bowing deformities of the legs. Patients

have normal serum Ca

with low P content due

to increase urine P

excretion (phosphate depletion resulting

from renal tubular

dysfunction).

Page 21

• Introduction

• Parathyroid

• Thyroid

• Vitamin D

• Bone turnover

• Pathologies



pathologies

Paget’s disease is

characterized by

marked focal increase in bone

resorption and

bone formation

resulting in

disorder bone architecture (e.g.

bowing of the

femur, bone

destruction and

soft tissue swelling). Viral

origin ??

• Introduction

• Parathyroid

• Thyroid

• Vitamin D

• Bone turnover

• Pathologies



pathologies

Paget’s disease is

characterized by

marked focal increase in bone

resorption and

bone formation

resulting in

disorder bone architecture (e.g.

bowing of the

femur, bone

destruction and

soft tissue swelling). Viral

origin ??

Page 22

• Introduction

• Parathyroid

• Thyroid

• Vitamin D

• Bone turnover

• Pathologies



pathologies

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