Chapter 6

Hormonal Control of Calcium

Homeostasis

Nam Deuk Kim, Ph.D.

1

1. Calcium and Bone Physiology

• Plasma Ca2+ must be closely regulated to prevent changes in

neuromuscular excitability

– Also plays vital role in a number of essential activities

• Neuromuscular excitability

• Stimulus-secretion coupling

• Excitation-contraction coupling in cardiac and smooth muscle

• Maintenance of tight junctions between cells

• Clotting of blood

– Hypercalcemia

• Reduces excitability

– Hypocalcemia

• Brings about overexcitability of nerves and muscles

• Severe overexcitability can cause fatal spastic contractions of

respiratory muscles

2

Endocrine Control of Calcium Metabolism

• Three hormones regulate plasma

concentration of Ca2+ (and PO43-)

– Parathyroid hormone (Parathormone, PTH)

– Calcitonin

– Vitamin D

3

Ca++:

PTH

V-D3

Ca++:

Calcitonin

Hydroxyapatite: Ca10(PO4)6(OH)2

4

Bone continuously undergoes remodeling.

5

Osteocyte

Osteon

Blood vessel

from marrow

Central

canal

Vessel in central canal

Canaliculi

Lamella

Central

canal

6

7

• Role of osteoblasts in governing

osteoclast development and activity

8

Osteoblast

Outer

surface

Osteocyte

Canaliculi

Osteocytic–

osteoblastic bone

membrane

Mineralized

bone

Bone fluid

Osteoblast

Blood vessel

Central canal

Lamellae

Relationship of mineralized bone, bone cells,

bone fluid, and the plasma

9

In canaliculi In central canal

Mineralized bone:

stable pool of Ca2+

Bone fluid:

labile pool

of Ca2+

Plasma

Fast exchange

Slow exchange

(Bone

dissolution)

= Membrane-bound

Ca2+ pump

Relationship of mineralized bone, bone cells,

bone fluid, and the plasma

10

Endocrine Control of Calcium Metabolism

• Parathyroid hormone (PTH)

– Secreted by parathyroid glands

– Primary regulator of Ca2+

• Raises free plasma Ca2+ levels

by its effects on bone kidneys,

and intestines

– Essential for life

• Prevents fatal consequences of

hypocalcemia

– Facilitates activation of Vitamin D

11

Fig. 9-1: Posterior (left) and transverse (right) views of

the human thyroid with attached parathyroids.

12

2. Parathormone

“Chief Cells”:

(주세포)

Parathyroid

Hormones

(Parathormone, PTH)

혈중 칼슘 농도

증가 유지

13

Fig. 9-2: Comparative structures of parathormone (PTH).

14

• Synthesis, chemistry, and metabolism of PTH

- A polypeptide 84 aa long, derived from a precursor

molecule of 115 aa.

- Preproparathyroid hormone (115 aa preproPTH) 90

aa proPTH 84 aa PTH

• Control of PTH secretion

- Release of PTH from the gland is controlled by

circulating levels of Ca2+

- Ca2+-sensing receptor [calcium-sensing receptor

(CaSR)] : a typical seven-spanning membrane G-

protein–coupled receptor

- Human Ca2+-sensing receptor: 1,018 aa with 93%

sequence similarity to the bovine receptor

15

Rough Endoplasmic Reticulum

consitutive synthesis Parathyroid Chief Cells

Pre Pro PTH PreproPTH

-31 -6 1 84 Cisternal space of RER

signal peptidase action

ProPTH

Golgi Apparatus

processing

PTH

Granules

packaging

Secretion

Low Ca2+

Prepro-PTH and its processing to secreted PTH in the parathyroid chief cells.

Negative numbers indicate the number of amino acids prior to the first amino

acid in PTH 16

• PTH acts to raise plasma

Ca2+ levels

- Bone mineral metabolism

- Renal reabsorption of

calcium

- Renal excretion of phosphate

- Intestinal absorption of

calcium

- Control of vitamin D

synthesis

- Other possible actions of

PTH: increases the mitotic

rate of red cell progenitors

(reticulocytes) and thymic

lymphocytes.

17

Interaction

between PTH

and V-D in

controlling

plasma calcium

18

Fig. 9-3: Aligned sequences of the 1–34 region of PTH and PTHrP

from various species. Conserved residues are outlined in black.

Note the lack of substantial sequence identity between PTH and

PTHrP from amino acid residue 14 through the C terminus.

3. Parathormone-related Peptide (PTHrP) • PTHrP: isolated from human tumor cells or tissues obtained

from patients with humoral hypercalcemia of malignancy

• PTHrP: 139-173 aa resides, depending upon the species.

19

Fig. 9-4: Primary structure of human calcitonin.

4. Calcitonin • Calcitonin

– Hormone produced by C cells of thyroid gland

– Negative-feedback fashion

• Secreted in response to increase in plasma Ca2+

concentration

– Acts to lower plasma Ca2+ levels by inhibiting activity

of bone osteoclasts

– Unimportant except during hypercalcemia

20

C cell (Calcitonin)

21

Fig. 9-5: Comparative structures of some calcitonins. Three

molecular species (isoforms) of salmon CT exist; the structure of

salmon I calcitonin is shown, which differs from eel CT at only

three residues (eel: 26, Asp; 27, Val; 29, Ala).

22

• Calcitonin acts to lower plasma Ca2+ levels

- Bone mineral metabolism:

- Calcitonin as a satiety hormone: Subcutaneous (s.c.)

injections of CT inhibit the 24-hour food intake of rats and

rhesus monkeys. Intracerebroventricular injections of CT in

the rat are also inhibitory to feeding. In humans, significant

reduction in body weight is observed 24 to 36 hours

following a single s.c. injection of CT.

- Vitamin D regulation: CT directly stimulates V-D metabolism

and indirectly stimulates it by lowering plasma Ca2+ levels,

resulting in the release of PTH, which activates renal

vitamin D synthesis and secretion.

23

Negative-feedback Loops Controlling Parathyroid

Hormone (PTH) and Calcitonin Secretion

24

25

26

5. Vitamin D

• Stimulates Ca2+ and PO43- absorption from

intestine

• Can be synthesized from cholesterol derivative

when exposed to sunlight

• Often inadequate source

• Amount supplemented by dietary intake

• Must be activated first by liver and then by kidneys

before it can exert its effect on intestines

27

Precursor in skin

(7-dehydrocholesterol) Dietary vitamin D

Vitamin D3

Hydroxyl group (OH)

Liver enzymes

25-OH D3

Hydroxyl group PTH Plasma Ca2+

Kidney enzymes

Plasma PO4 3-

1, 25-(OH)2 D3

(active vitamin D)

Promotes intestinal absorption of Ca2+ and PO4

+

3-

Sunlight

Activation of

Vitamin D

28

Fig. 9-6: Photic stimulation of integumental cholecalciferol

(vitamin D3) formation and subsequent transfer to the general

circulation by a cholecalciferol-binding protein.

29

Fig. 9-7: Production of ergosterol and ergocalciferol from

their precursors.

30

Fig. 9-8: Sequential

steps in the

biosynthesis of

vitamin D.

31

Fig. 9-9: Feedback control of vitamin D biosynthesis. 32

• V-D promotes Ca2+

absorption in the gut and

Ca2+ reabsorption in the

kidney.

- Intestine:

- Bone:

- Kidney:

- Other putative roles:

33

Interaction

between PTH

and V-D in

controlling

plasma calcium

34

Control of

plasma

phosphate

35

36

6. Hormone Mechanisms of Action in

Calcium Homeostasis

Fig. 9-10: Cell-surface receptors for PTH are coupled to two classes of G proteins. Gs

mediates stimulation of adenylyl cyclase (AC) and the production of cAMP, which in turn

activates protein kinase A (PKA). Gq stimulates phospholipase C (PLC) to form the second

messengers inositol-(1,4,5)-triphosphate (IP3) and diacylglycerol (DAG) from membrane-

bound phosphatidyl-inositol-(4,5)-biphosphate. IP3 increases intracellular calcium (Ca2+) and

DAG stimulates protein kinase C (PKC) activity. Each G protein consists of a unique chain

and dimer.

1) PTH

37

Regulation of PTH secretion • Secretion of parathyroid hormone is

controlled chiefly by serum [Ca2+] through

negative feedback.

• Calcium-sensing receptors located on

parathyroid cells are activated when

[Ca2+] is low.

• The G-protein coupled calcium receptors

(CaR) sense extracellular calcium and

may be found on the surface on a wide

variety cells distributed in the brain, heart,

skin, stomach, C cells, and other tissues.

• In the parathyroid gland, sensation of

high concentrations of extracellular

calcium result in activation of the Gq G-

protein coupled cascade through the

action of phospholipase C.

• This hydrolyzes phosphatidylinositol 4,5-

bisphosphate (PIP2) to liberate

intracellular messengers IP3 and

diacylglycerol (DAG).

• Ultimately, these two messengers result

in a release of calcium from intracellular

stores and a subsequent flux of

extracellular calcium into the cytoplasmic

space.

• The effect of this signaling of high

extracellular calcium results in an

intracellular calcium concentration that

inhibits the secretion of preformed PTH

from storage granules in the parathyroid

gland.

• In contrast to the mechanism that most

secretory cells use, calcium inhibits

vesicle fusion and release of PTH.

38

• Stimulators of PTH secretion

- Decreased serum [Ca2+].

- Mild decreases in serum [Mg2+].

- An increase in serum phosphate

(increased phosphate causes it to

complex with serum calcium, forming

calcium phosphate, which reduces

stimulation of Ca-sensitive receptors

(CaSr) that do not sense calcium

phosphate, triggering an increase in PTH)

• Inhibitors of PTH secretion

- Increased serum [Ca2+].

- Severe decreases in serum [Mg2+], which

also produces symptoms of

hypoparathyroidism (such as

hypocalcemia).

- Hypermagnesemia

- Calcitriol

39

• In the parathyroids, magnesium

serves this role in stimulus-

secretion coupling.

• Magnesium: a natural calcium

antagonist

• Hypomagnesia inhibits PTH

secretion and also causes

resistance to PTH, leading to a

form of hypoparathyroidism that is

reversible.

• Hypermagnesemia also results in

inhibition of PTH secretion when a

moderate low calcium

concentration is present.

40

“Magnesium and the parathyroid”

• Curr Opin Nephrol Hypertens. (2002)

11(4): 403-410.

• The serum levels of parathyroid hormone

and magnesium depend on each other in

a complex manner.

• The secretion of parathyroid hormone by

the parathyroid is physiologically

controlled by the serum calcium level, but

magnesium can exert similar effects.

• While low levels of magnesium (mild

decrease) stimulate parathyroid hormone

secretion, very low serum concentrations

(hypomagnesemia) induce a paradoxical

block.

• This block leads to clinically relevant

hypocalcemia in severely

hypomagnesiemic patients.

• The mechanism of this effect has recently

been traced to an activation of the alpha-

subunits of heterotrimeric G-proteins.

“Magnesium modulates parathyroid

hormone secretion and upregulates

parathyroid receptor expression at

moderately low calcium concentration”

• Nephrol Dial Transplant (2014) 29: 282–

289

• Results:

I. Increasing Mg concentrations from 0.5 to

2 mM produced a left shift of PTH–Ca

curves.

II. With Mg 5 mM, the secretory response

was practically abolished. Mg was able

to reduce PTH only if parathyroid glands

were exposed to moderately low Ca

concentrations; with normal–high Ca

concentrations, the effect of Mg on PTH

inhibition was minor or absent.

• Conclusions. Mg reduces PTH secretion

mainly when a moderate low calcium

concentration is present; Mg also

modulates parathyroid glands function

through upregulation of the key cellular

receptors CaR, VDR and FGF23/Klotho

system.

IL-6 Gs cAMP PKA

IL-6; other

cytokines

ODF

Osteoblast

Bone constructor

Osteoclast

Bone destructor

Control of bone remodeling by PTH and calcitonin

activation CT PKA cAMP

inactivation PTH

Gs

• Calcitonin (CT) secreted by thyroid C-cells in response to hypercalcemia.

• CT gene can yield calcitonin gene-related peptide (CGRP) if processed

differently (alternative mRNA splicing).

• CGRP = a potent vasodilator

2) Calcitonin (CT): Receptors for CT are present in skeletal tissue,

kidney, and testicular Leydig cells.

41

Receptor for calcitonin

• The calcitonin receptor, found on

osteoclasts, and in kidney and

regions of the brain.

• G protein-coupled receptor, which

is coupled by Gs to adenylate

cyclase and thereby to the

generation of cAMP in target cells.

• It may also affect the ovaries in

women and the testes in men.

• Calcitonin can be used

therapeutically for the treatment

of hypercalcemia or osteoporosis.

• Oral calcitonin may have a

chondroprotective role in

osteoarthritis (OA) How

calcitonin affects osteoarthritis

(OA)?

Calcitonin acts both directly on

osteoclasts, resulting in inhibition of

bone resorption and following

attenuation of subchondral bone

turnover, and directly on

chondrocytes, attenuating cartilage

degradation and stimulating

cartilage formation

42

Uses of calcitonin

Fig. 9-11: Mechanism of action and general functions of 1,25(OH)2D3 in target cells.

3) Vitamin D

43

Fig. 9-12: Generalized model of the role of hormones controlling bone

mineralization and demineralization.

7. Hormone Integration in Calcium Homeostasis

44

Fig. 9-13: Primary structure of calmodulin (CaM), an intracellular

calcium receptor. The following are one-letter codes for amino acid

residues: A, Ala; D, Asp; E, Glu; F, Phe; G, Gly; H, His; I, Ile; K, Lys; L,

Leu; M, Met; N, Asn; P, Pro; Q, Gln; R, Arg; S, Ser; T, Thr; V, Val; Y,

Tyr.

8. Hormonal Regulation of Intracellular Calcium

45

Calcium release in excitation-contraction coupling.

46

Fig. 9-14:

Model for the

mechanism of action of

calmodulin.

47

9. Pathophysiology 1) Hypoparathyroidism results in hypocalcemia.

2) Hyperparathyroidism results in hypercalcemia.

3) Hypercalcemia can accompany some malignancies.

4) Osteomalacia is a condition of inadequate bone mineralization.

5) Paget’s disease is characterized by excess osteoclastic activity.

6) Osteoporosis is a condition of decreased bone mineral density.

a. Postmenopausal (Type I) osteoporosis

b. Senile (Type II) osteoporosis

7) New pharmacological therapies for diseases of Ca2+ homeostasis

are available.

a. Bisphosphonates

b. Selective estrogen receptor modulators (SERMs)

c. Pharmaceutical preparations of vitamin D.

d. Dietary calcium and osteoporosis

48

Parathyroid Glands

Calcium Metabolism

• Blood calcium is in equilibrium with calcium in the bone

• Calcium level is regulated by the parathyroid glands

– Reduced calcium in blood: tetany (increases neuromuscular excitability, causing spasm of skeletal muscle)

– Elevated calcium in blood: reduces neuromuscular excitability

49

Calcium Disorders

• PTH hypersecretion (hyperparathyroidism)

– Characterized by hypercalcemia and

hypophosphatemia

• PTH hyposecretion (hypoparathyroidism)

– Characterized by hypocalcemia and

hyperphosphatemia

• Vitamin D deficiency

– Children – rickets

– Adults – osteomalacia

50

51

Completed Picture of Updated Calcium/Parathyroid Hormone

Normogram (http://www.parathyroid.com/hyperparathyroidism-

diagnosis.htm, 2014.4.6)

Hyperparathyroidism

• Usually a result of hormone-secreting

parathyroid adenoma

• Blood calcium rises

• Excessive calcium withdrawn from bone

• Excessive calcium excreted in urine

• Treated by removal of tumor

52

원발성 부갑상샘 기능항진증

(Primary Hyperparathyroidism)

: PTH 과다분비

원인:

1. 샘종(80%)

2. 원발성 증식증(10~15%)

3. 샘암종(5% 이하)

53

부갑상샘 기능항진증

조직학적 변화

1. Adenoma

2. Primary hyperplasia:

Chief cell

3. Primary hyperplasia:

Clear cell

4. Secondary hyperplasia

5. Carcinoma

54

부갑상샘 기능항진증

임상 증상

1. 혈중 PTH 상승

2. 고칼슘혈증

3. 저인산염혈증

4. 낭종섬유성 골염

5. 신장결석

6. 정서적 불안

7. 기억력 감퇴

8. 근 약화

9. 전이성 칼슘 침착

10. 위장의 소화성 궤양

55

고칼슘증 감별 진단법

1. Hyperparathyroidism

2. Milk-Alkali syndrome

3. V-D intoxication

4. Sarcoidosis

5. Multiple myeloma

6. Metastatic ca.

7. Primary ca, not involving

bone

8. Disuse atrophy

(osteoporosis)

9. Thyrotoxicosis

56

Hypoparathyroidism

• Usually result of removal of parathyroid glands

during thyroid surgery

• Blood calcium falls precipitously

• Leads to neuromuscular excitability and tetany

• Treated with high-calcium diet and

supplementary vitamin D

57

부갑상샘기능저하증

(Hypoparathyroidism)

: 혈중 저칼슘증 발생

1. 갑상샘 절제술

2. 특발성

3. 가족성

4. 가성: PTH에 대한 무감응

58

임상증상:

• 저칼슘혈증

• 근-신경 흥분성

• Trousseau’s sign

• Chvostek’s sign

• Convulsion

• Laryngeal spasm

• Choked disk

• 정서불안

• 정신병

부갑상샘기능저하증

(Hypoparathyroidism)

59

골연화증/구루병

• 골연화증(Osteomalacia): 새로이 형성된 뼈 기질에 미네랄화가 부적절한 것을 특징으로 하는 성인 질환

• 구루병(Rickets): 골단이 열려 있는 어린이에서 발생하는 유사질환

• 비타민 D 대상의 비정상, 인산 결핍 상태 및 미네랄화 과정 자체의 결함 등

60

•골연화증 (Osteomalacia) •구루병(Rickets)

61

62

Paget's disease of bone • Paget's disease of the bone (other terms are Paget's disease, osteitis

deformans, osteodystrophia deformans): a chronic disorder that typically

results in enlarged and deformed bones.

• The disease is named after Sir James Paget, the British surgeon who first

described it in 1877.

• The excessive breakdown and formation of bone tissue that occurs with Paget's

disease can cause bone to weaken, resulting in bone pain, arthritis, deformities, and

fractures.

• Paget's disease is rarely diagnosed in people less than 40 years of age. Women are

more commonly affected than men.

• Prevalence of Paget's disease ranges from 1.5 to 8.0 percent, depending on age

and country of residence. Prevalence of familial Paget's disease (where more than

one family member has the disease) ranges from 10 to 40 percent in different parts

of the world.

• Because early diagnosis and treatment is important, after age 40, siblings and

children of someone with Paget's disease may wish to have an alkaline

phosphatase blood test every two or three years.

• If the alkaline phosphatase level is above normal, other tests such as a bone-

specific alkaline phosphatase test, bone scan, or X-ray can be performed.

63

뼈의 파제트병 Paget Disease of Bone

64

65

Urinary

hydroxyproline

elevated

66

Osteoporosis

• Generalized thinning of the bone and dimineralization of the entire skeletal system, “porous bones”

– Most common in postmenopausal women

• Loss of estrogen accelerates rate of bone resorption

– Also develops in elderly men

• Remember that osteoporosis is not the same as osteoarthritis

• Osteoarthritis is the “wear and tear” degeneration of one or more of the weight-bearing joints

67

68

69

70

Russian spotters carry astronaut Ken Bowersox at the landing

site of the Soyuz space capsule that returned him and two

others to Earth.

It was a dramatic end to a 5 1/2-

month space station mission for

Ken Bowersox, who served as the

commander, astronaut Donald

Pettit and cosmonaut Nikolai

Budarin.

May 4, 2003

골다공증

71

72

73