Three hormones play significant role in calcium and phosphate homeostasis:
1. Calcitriol (1,25 dihydroxy cholecalciferol)
2. Parathyroid Hormone (PTH)
Other related hormones include:
1. Parathyroid hormone related protein (PTHr P):
Acts on PTH receptors & skeletal development in utero.
Increase bone resorption
3. Growth Hormone
4. Estrogen & Androgens:
5. Growth Factors etc.
Stimulate osteoblasts and formation of bone matrix.
6. Thyroxin acting along with the growth hormone.
Calcium ion concentration is regulated by:
i. Ca++ absorption from intestines,
ii. Renal excretion of Ca++
iii. Bone resorption / formation i.e. uptake & release of Ca++.
Calcitriol (Viatmin D3)
Vitamin D3 itself is not active, unless changed into 1,25 (OH)2 D3 in kidneys through liver.
Vitamin D3 is a fat soluble vitamin. It is taken in the food and also synthesized by the skin. 7-dehydrocholesterol is converted by ultravoilet light falling on skin into vitamin D3.
Vitamin D3 in the form of cholecalciferol is inactive. It is converted by liver into 25-hydroxy D3 which is stored in liver. 25-hydroxy D3 is converted into 1,25-hydroxy D3 by the kidneys.
Vitamin D3 has several potent effects;
1. Active transport of Ca++ & PO4-3 from intestine
2. On bone deposition & resorption
3. Facilitates reabsorption in kidneys
4. An increase in activity of osteoblasts (leading to increase in bone matrix), differentiation of immune cells & keratinocytes in skin.
Transport in plasma:
Calcitonin is transported in the plasma bound to globulin.
• Vit D3 is hormone; as it is produced in body,transported in blood & acts on target cells. It acts through nuclear transcription & ribosomal
translation, resulting in formation of proteins.
Parathyroid Hormone (PTH)
Four parathyroid glands are present in humans located behind upper & lower poles of thyroid gland. Each parathyroid gland is 6 mm x 2 mm and are difficult to locate because appear as dark brown fat. Parathyroid gland might be removed with thyroidectomy.
Adult parathyroid glands contain:-
i. Chief cells:
Present in maximum numbers and secrete parathyroid hormone
ii. Oxyphil cells:
Present in moderate numbers and are depleted chief cells which has ceased to secrete PTH.
Synthesis/Chemistry of PTH:
PTH is a polypeptide, containing 80 amino acids. It is synthesized as preprohormone (containing 110 amino acids) in Ribosomes. It is cleaved to prohormone (containing 90 amino acids) and then to PTH (containing 80 amino acid)
It is stored in secretory granules.
Mechanism of Action of PTH:
PTH acts via adenyle cyclase – cAMP dependent 2nd messenger system in osteocytes, osteoblasts, osteoclasts & target cells (e.g. in kidneys)
PTHrP acts via phospholipase dependent 2nd messenger system.
Control of PTH secretion
The control of parathyroid hormone secretion occurs by negative feedback mechanism, which is sensitive to Ca++ concentration in plasma. Even slightest decrease in ECF [Ca++] increases PTH secretion, whereas prolonged decreased [Ca++] causes the parathyroid gland to hypertrophy(5 Fold).
Some examples include:
1. In Rickets.
2. In Pregnancy
3. In lactation
Increased [Ca++] above normal decreases activity and size of parathyroid gland
Some examples include:
1. Excess intake of Ca++
2. Increased intake of Vitamin D.
3. Bone resorption as in some bone diseases
Actions of PTH:
1.Direct action on bone:
Increases bone resorption i.e. increased Ca++ & PO4 absorption from bones. This occurs in two phase:
a. Rapid Phase:
This phase starts in minutes, progresses for hours by activation of already existing bone cells (Osteocytes). PTH removes bone salts from two areas:
i. From bone matrix in the vicinity of osteocytes within bone
ii. In the vicinity of osteoblasts along bone surface
b. Slow Phase:
This phase takes days & weeks to develop by:
i. Proliferation of Osteoclasts and
ii. Increased Osteoblastic resorption of bone itself
PTH receptors are present on osteocytes & osteoblasts
Osteocytic membrane pumps Ca++ from “bone fluid” into ECF creating [Ca++] in bone fluid only 1/3rd of that in ECF.This pumping Ca++ from bone fluid into ECF is called “Osteolysis”
Decreased Excretion of Ca and Increased Excretion of PO4 by Kidneys:
Parathyroid hormone increases renal tubular reabsorption of Ca++ by late distal tubules and collecting ducts takes place, as well as decreased proximal tubular reabsorption of PO4.
Also an increase in reabsorption of Mg++ & H+ take place accompanied by decreased reabsorption of Na+, K+ & amino acids like phosphate.
3. Increased Absorption of Ca++, PO4 in Intestines:
This occurs by formation of 1,25 (OH)2 D3 in kidneys from Vit D.
Calcitonin is secreted by the para follicular cells or C-cells of the thyroid gland (C-cells constitute 0.1% of human thyroid gland). Calcitonin is a peptide hormone, consisting of 32 amino acids and has a molecular weight of about 3400. Its half life is about 10 minutes.
An increase in plasma Ca++ concentration i.e. >9.5mg/dl stimulates Calcitonin secretion (10% increase in plasma Ca++ causes a two fold increase in Calcitonin)
Calcitonin tries to lower plasma Ca++ and PO4 concentration (i.e. it inhibits bone resorption). Its effect is quantitatively far less than that of PTH in regulation of Ca++ concentration in adults; because initial decrease in Ca++ concentration by calcitonin leads to a powerful stimulation of PTH. Thus PTH overrides the effect of calcitonin.
Effect of calcitonin in children is greater because bone remodeling occurs rapidly and absorption as well as deposition of calcium is as great as 5 gm/day (equal to 5-10 times the total calcium in all the extracellular fluid)
I. Effect on bone:
Calcitonin decreases plasma Ca++ by two ways:-
a. Immediate Effect: (in minutes)
It inhibits absorptive activities of osteoclasts which leads to increased Ca++ deposition in exchangeable bone Calcium salts. This protects against postprandial hypercalcemia. It also protects bones of mother from excessive loss during pregnancy & lactation (there is an increase in 1,25 dihydroxycholecalciferol during pregnancy)
b. Prolonged Effect:
Calcitonin causes decreased formation of new osteoclasts. The decreased number of osteoclasts lead to a decrease in number of osteoblasts. Therefore, activity of both the cells is decreased (in hours or days).
Thus calcitonin has very little prolong effect on plasma calcium ion concentration.
II. Effects on kidneys & GIT:
Calcitonin plays only a minor role in Ca++ handling by renal tubules and intestines.