calcium

1Calcium: essential for normal physiological function

- essential mineral component of the skeleton and teeth

- intracellular 2nd messenger

plays central role in muscular contraction, blood coagulation, enzyme

activity, neuronal excitability, hormone secretion, cell adhesion, etc.

Calcium Metabolism:

- 99% of body calcium: in inorganic, mineralized matrix of

bone as hydroxyapatite Ca10

(PO4)6(OH)

2

- most of the rest is intracellular in endoplasmic reticulum

of cells

- extracellular fluid (ECF) contains 0.1% at about

2.5mmol/l

Calcium Homeostasis

Complexed Ca2+

45%

5%

50% Ionised Ca2+

Protein bound

Diffusible

Non-diffusible

pH dependent

acid

alkaline

1. structural integrity of bone and teeth

2. 2nd messenger or regulatory ion (co-factor for enzymes)

10,000 fold Ca2+ concentration gradient between ECF and cytoplasm

permits Ca2+ to function as signalling ion to activate intracellular processes

Ca2+ influx into the cytoplasm is controlled by Ca2+ channels

Influx of Ca2+ into cells:

- regulates cellular function by interaction with intracellular calcium binding

proteins and calcium-sensitive protein kinases

- stimulates biological responses such as neurotransmitter release, contraction,

secretion

Uncontrolled cellular Ca2+ entry VERY bad!

Functions of Calcium

Kidney

reabsorbs 98%

of filtered Ca2+

Bone

remodeling; two sources :

1) readily mobilizable Ca2+-salts in the ECF

2) hydroxyapatite [Ca10

(PO4)6(OH)

2] crystals

Daily Ca2+ balance:

- gains: only from diet

- losses: urine, faeces, lactation

- exchange: bone remodelling

Calcium Homeostasis

Three important tissues:

Gut

absorption from

diet

2Daily Calcium Balance

3 Hormones:

parathyroid hormone (PTH)

calcitonin

1, 25 dihydroxycholecalciferol

(1,25 DHCC, calcitriol,

active vitamin D)

Balance maintained by the action of hormones

Parathyroid Gland

parathyroid chief cells

thyroid

Parathyroid Hormone Secretion

Regulation of PTH secretion by Ca2+ (minute-to-minute fine regulation)

- PTH protein stored in secretory granules of chief cells

3Parathyroid Hormone

Biological effects of PTH:

- primary target cells in bone and kidney

1) elevate blood concentrations of Ca2+

2) increase kidney tubular reabsorption of Ca2+, i.e. decrease loss in urine

3) increase Ca2+ release from osteoblasts (rapid response)

4) accelerate the formation of the principal active vitamin D metabolite (1, 25 DHCC) in

tubule epithelial cells (well get to this later!)

Parathyroid Hormone Effects on Bone

Fast exchange = release from labile pool

Slow exchange = bone dissolution through osteoclast activity

Parathyroid Hormone Effects on Bone: Fast Exchange

2Na+

Ca2+Ca2+

Parathyroid Hormone Effects on Bone: Slow Exchange

PTH

Osteoblast

RANK Ligand

Maturation of osteoclasts Bone resorption

4Calcitonin

- secreted by a population of endocrine cells in the thyroid gland called C-cells (distinct

from follicular cells that secrete thyroid hormone!)

Regulation of secretion:

- secretion rapidly increases in response to elevation in blood Ca2+

- longer-term hypercalcemia causes increases in secretory granule machinery

C-cells

Calcitonin Action

Biological effects of Calcitonin:

Prevent hypercalcemia!

primary target tissue: bone and kidney; to a lesser degree intestinal cells

reduce blood Ca2+ levels

1) inhibits bone resorption (decreased entry of Ca2+ from the skeleton into plasma)

2) reduces Ca2+ reabsorption in kidneys

Integration of PTH and Calcitonin:

- PTH is the major factor concerned with minute-to-minute regulation of blood Ca2+ levels

and protection from hypocalcemia

- calcitonin is more of an emergency hormone to

- 1) prevent hypercalcemia after postprandial absorption of Ca2+ and

- 2) protect against excessive loss of Ca2+ from the maternal skeleton during

pregnancy

1, 25 dihydroxycholecalciferol (a.k.a. 1, 25 VitaminD3, calcitriol)

Produced in the proximal convoluted tubule cells of the kidney

Steroid produced from cholesterol..

. Or from diet dairy products/fortified cereal breads

Biological function (longer-term regulation of Ca2+ homeostasis):

increase absorption of Ca2+ from intestine

protect bone!

Ca channels

Calbindin

Pumps

Exchangers

1, 25 dihydroxycholecalciferol (a.k.a. 1, 25 VitaminD3, calcitriol)

kidney

1,25 DHCC

calcitriol

vitamins, but can be considered hormones

diet

calciferol-25-hydroxylase

renal 1-hydroxylase

PTH

5 Diet deficient in Vitamin D and lack of sunlight

renal 1-hydroxylase deficiency (autosomal recessive

disease)

Rickets (Children) and Osteomalacia (Adults)

Vitamin D mum test 'could protect babies from rickets' BBC 19thAugust 2011

By Adam Brimelow Health Correspondent, BBC News The NHS should consider checking pregnant women's vitamin D levels to protect babies from

the "Victorian" bone disease rickets, an expert says.

Disorders of Calcium Homeostasis - Vitamin D deficiency

Active

Vitamin D

Calcium uptake in gut

Cartilage not properly mineralised;

weak, malformed bones

Calcium resorbed

from bonePTH

Hyperparathyroidism

Excessive PTH secretion by parathyroid glands

Primary Hyperparathyroidism:

parathyroid cells secrete unregulated, excessive amounts of PTH, e.g. adenomas of

chief cells

Demineralized bone of the foreleg of a dog with

primary hyperparathyroidism.

Cortical bone is thin and there are areas of osteal

resorption (arrows) .

Disorders of Calcium Homeostasis -

PTH

Calcium resorbed

from bone

Calcium uptake in

kidney

Decrease in bone density

Multiple fractures

Secondary Hyperparathyroidism: (most common)

renal: chronic renal failure leading to increased (excessive) PTH secretion

Hyperparathyroidism

Kidney

Function

PTH

Disorders of Calcium Homeostasis -

Ca retention in

kidney

Calcitriol

production

Ca absorbtion

in gut

Hypocalcaemia

bone deformation and

fractures

X

Disorders of Calcium Homeostasis - Hypoparathyroidism

Inadequate PTH secretion:

e.g. inadvertent removal of parathyroid gland during thyroid surgery

PTH

Ca retention in

kidney Calcitriol

production

Ca absorbtion

in gut

Hypocalcaemia

Bone

resorption

increased neuromuscular excitability (due to decreased threshold of excitation),

paresthesia and tetany; abnormalities in enamel formation