Post on 16-Dec-2015
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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