In this article we will discuss about the role of PTH and Vit. D3 in calcium metabolism.
Role of PTH in Calcium Metabolism:
Hypocalcemia in blood stimulates parathyroid gland for PTH secretion.
During calcium metabolism, it shows following functions—
1. On bones:
Drop of Ca++ level in blood, stimulates PTH secretion. PTH uses bones as Ca++-bank from which it withdraws Ca++.
PTH performs its function following was:
(a) PTH stimulates osteoclasts to increase the resorption of bones and the dissolution of both organic and inorganic phases of bone cells; it enhances the mobilization of Ca++ from bones to blood. During this mechanism, number, activity and microvilli as well as lysosomal hydrolases and carbonic anhydrase activities are increased.
(b) PTH also stimulates the differentiation and maturation of precursor cells of osteoclasts.
(c) It stimulates the resorption of bones by osteocytes with the consequent release of bone minerals into blood.
(d) Higher concentration of PTH inhibits alkaline phosphatase in osteoblasts as well as collagen synthesis in bones, thereby decreasing the Ca++ retaining capacity of bones.
(e) Low concentration of PTH enhances alkaline phosphatase activity in osteoblasts and helps in forming and re-modeling of bones.
PTH initially activates membrane bound Ca++ pumps, located in the plasma membranes of osteoblasts and osteocytes in presence of adenyl cyclase and ATP (Fig. 10.1). These pumps promote movement of Ca++ from the bone fluid across the osteocytic-osteoblastic bone membrane into the plasma. The fast and slow exchange of Ca++ takes place through osteocytic-osteoblastic bone membrane.
In the fast exchange, Ca++ is moved from the labile pool in the bone fluid into the plasma by means of PTH activated Ca++ pumps. In a slow exchange Ca++ is moved from the stable pool in the mineralized bone into the plasma by means of PTH-induced dissolution of the bone (Fig. 10.1 and Fig. 10.2).
2. On kidney:
The effect of PTH is more quicker on kidney than bones.
The renal effects of PTH are as follows:
(a) PTH decreases the renal clearance of Ca++. It enhances the trans-membrane transport and reabsorption of the filtered Ca++.
(b) In renal proximal tubular cells, PTH increases the activity of mitochondrial mixed function oxidase, and 25(OH) D3 1 α-hydroxyls, to enhance the renal formation of Vit. D3, which in-turn increases intestinal absorption of Ca++.
3. On intestine:
PTH increases intestinal absorptions of dietary Ca++ and PO3-4 PTH has no direct effect on the intestine, it indirectly increases both Ca++ and PO3-4 absorption from the small intestine by means of its role in Vit. D activation.
Experiments: In Ca++ metabolism CT and PTH play an antagonistic function to maintain homeostatic blood calcium level (Figs. 10.3 and 10.4).
Experiments were conducted on dog to demonstrate the role of thyroid and parathyroid gland on Ca++ metabolism. In the first phase of experiment, a dog was injected with Ca++ in the blood. Graph showed that one hour before injection Ca++ concentration in the blood was normal. At time of injection concentration raised. About 6 hrs. later, the concentration was normal. Therefore some agent was probably reducing the flow of Ca++ from the bone into the blood (Fig. 10.5).
The same dog was then injected with a chelating agent that captures Ca++ in blood and renders it inactive. The graph showed that one hour before the injection the Ca++ concentration was normal. After the injection it was depressed.
About 6 hrs. after the injection, the concentration was normal again as was expected because a hormone secreted by the parathyroid gland was known to elevate the Ca++ concentration in the blood (Fig. 10.6).
In the second phase of experiment, thyroid and parathyroid ectomised dog was injected with Ca++. The graph indicated that Ca++ concentration, which was normal one hour before the injection, quickly raised (Fig. 10.7).
More than 24 hrs. later the concentration was still high, indicating that some agent that normally reduced the concentration was no longer present because the glands were missing. Later a chelating agent was injected, the Ca++ concentration was normal one hour earlier was depressed. More than 24 hrs. later the concentration was still low, because the PTH which kept the concentration high had been eliminated by removal of the gland (Fig. 10.8).
Role of Vitamin D3 in Calcium Metabolism:
Vit. D is popularly known as sunshine vitamin. It is a fat soluble vitamin and is involved in the regulation of Ca++ metabolism. PTH enhances the activation of Vit. D in Ca++ metabolism. Vit. D is biologically inactive when it first enters the blood from either the skin or the digestive tract. It must be activated by two sequential biochemical alterations that involve the addition of two hydroxyl (-OH) groups.
Vit. D exists in two forms, a synthetic one, ergocalciferol (Vit. D2) and the natural material, cholecalciferol (Vit. D3) which is precursor or pro-hormone. Cholecalciferol is converted in the liver into 25-hydroxy cholecalciferol (25-OHD3).
This steroid is further hydroxylated in the kidney into active hormonal substance 1, 25-di-hydroxycholecalciferol (1, 25-(OH) 2D3). An increased production of 1, 25-(OH)2D3 can be stimulated by PTH, which is secreted in response to hypocalcemia, probably by decreasing the inorganic phosphorus levels in the renal cells (Fig. 10.9).
Like hormones, Vit. D3 is carried by blood to its target organs (bones, kidney and intestinal mucosa). It forms Vit. D3-receptor complex, this complex is trans located to the nucleus. Vit. D3 induces RNA-transcription and the synthesis of proteins including the calcium binding protein, calbindin D28 (Fig. 10.10).
Role of Vit. D3 in Ca++ regulation are given below:
1. On intestinal mucosa:
Vit. D3 stimulates trans epithelial Ca++ transport in the intestine by stimulating Ca++ entry. With the help of calbindin D28, Ca++ uptake in the intestinal cells increased by active transport mechanism.
2. On kidney:
Vit. D3 also stimulates reabsorption of Ca++ by the renal tubules with the help of carrier protein.
3. On bones:
The bones are the sites where Vit. D3, PTH and CT, interact with each other to promote or inhibit the resorption into the blood of calcium and phosphate. Vit. D3 increases the mobilization of Ca++ from bones to increase serum Ca++ level. Mobilization is increased by PTH and reduced by CT (Fig. 10.10).