BIOCHEMISTRY: A TEXTBOOK FOR MEDICAL UNIVERSITIES - E. S. Severin - 2004

CHAPTER 11. HORMONAL REGULATION OF METABOLISM AND BODY FUNCTIONS

VII. Regulation of Calcium and Phosphate Metabolism

The adult human body contains an average of 1,000 g of calcium. The primary calcium reservoir in the body (accounting for 99% of total body calcium) is the Skeleton. Roughly 99% of this bone calcium exists in the form of poorly soluble hydroxyapatite crystals [Са₁₀(РО₄)₆(ОН)₂Н₂О]. Only 1% of the calcium in bones is present as phosphate salts, which can readily exchange and act as a buffer against fluctuations in plasma calcium concentrations. The remaining calcium pool (1% of the total body mass) is found in Blood Plasma. Calcium enters the blood plasma from the intestines (via Water and food) and from Bone tissue (through The process of resorption).

Calcium is far more than just a structural component of bone tissue. Calcium Ions play a critical role in Muscle contraction, increase Cell membrane permeability to potassium ions, influence cellular sodium conductivity and the function of ion pumps, promote hormone secretion, and participate in the Blood Coagulation cascade. Furthermore, they serve as essential secondary messengers in Intracellular Signaling pathways.

Intracellular calcium concentrations depend directly on its level in the extracellular fluid. In healthy individuals, total plasma Ca²⁺ concentrations typically range from 2.12 to 2.6 mmol/L (or 9 to 11 mg/dL). Calcium exists in blood plasma in the following forms:

✵ unbound, ionized calcium (approximately 50%);

✵ calcium ions bound to Proteins, primarily albumin (45%);

✵ non-dissociated complexes with citrate, sulfate, phosphate, and carbonate (5%).

Ionized calcium represents the biologically active fraction, with its concentration strictly maintained between 1.1 and 1.3 mmol/L.

Alterations in calcium levels can disrupt numerous physiological processes, including shifting the excitation threshold of nerve and muscle Cells, impairing calcium pump function, reducing enzyme activity, and interfering with the hormonal REGULATION OF METABOLISM. Plasma Ca²⁺ concentration is regulated with exceptional precision: even a 1% deviation triggers homeostatic mechanisms to restore equilibrium.

The primary regulators of blood Ca²⁺ metabolism are parathyroid hormone, calcitriol, and Calcitonin.

A. Parathyroid Hormone

Parathyroid hormone (PTH) is a single-chain polypeptide consisting of 84 amino acid residues (approximately 9.5 kDa) designed to increase plasma calcium ion concentrations while decreasing plasma phosphate levels.

1. Synthesis and Secretion of PTH

PTH is synthesized in the Parathyroid glands as a precursor, preproparathyroid hormone, which contains 115 amino acid residues. During transport into The Endoplasmic reticulum, a 25-amino-acid signal peptide is cleaved from the preprohormone. The resulting prohormone is transported to the Golgi apparatus, where it is converted into the mature hormone consisting of 84 amino acid residues (PTH_1-84). Parathyroid hormone is then packaged and stored in secretory granules (vesicles). Intact parathyroid hormone may be cleaved into shorter Peptides: N-terminal, C-terminal, and mid-region fragments. The N-terminal peptides, comprising 34 amino acid residues, retain full biological activity and are secreted by the glands alongside the mature hormone; the N-terminal peptide is specifically responsible for binding to receptors on target cells. The precise Physiological Role of the C-terminal fragment remains unclear. The rate of hormone degradation decreases during periods of low calcium ion concentration and increases when calcium levels are high.

PTH secretion is regulated by the level of calcium ions in the plasma, with the hormone being released in response to a drop in blood calcium concentration.

2. Role of Parathyroid Hormone in The regulation of Calcium and Phosphate Metabolism

The target Organs for PTH are the bones and Kidneys. Specific receptors located on the Cells of the kidneys and bone tissue interact with parathyroid hormone, initiating a cascade of events that leads to the activation of adenylate cyclase. This increases intracellular cAMP levels, the action of

which stimulates the mobilization of calcium ions from intracellular stores. Calcium ions activate Kinases, which in turn phosphorylate specific proteins that induce the Transcription of target genes.

In bone tissue, PTH receptors are found on osteoblasts and osteocytes, but are absent on osteoclasts. Upon binding to target cell receptors, parathyroid hormone stimulates osteoblasts to secrete Insulin-like growth factor 1 and cytokines. These substances stimulate the METABOLIC ACTIVITY OF osteoclasts—specifically accelerating The production of Enzymes such as alkaline phosphatase and collagenase. These enzymes degrade bone matrix components, leading to the mobilization of Ca²⁺ and phosphates from the bone into the extracellular fluid (Fig. 11-37).

Class="center">Fig. 11-37. BIOLOGICAL EFFECTS OF parathyroid hormone. 1 — stimulates calcium mobilization from bone; 2 — promotes calcium ion reabsorption in the distal renal tubules; 3 — activates the synthesis of calcitriol [1,25(OH)₂D₃] in the kidneys, which enhances intestinal Ca²⁺ absorption; 4 — increases calcium concentration in the extracellular fluid and inhibits PTH secretion. ECF — extracellular fluid.

In the kidneys, PTH stimulates calcium reabsorption in the distal convoluted tubules, thereby reducing urinary calcium excretion while decreasing phosphate reabsorption.

Additionally, parathyroid hormone induces the synthesis of calcitriol [1,25(OH)₂D₃], which enhances calcium Absorption in the gut.

Thus, parathyroid hormone restores normal calcium ion levels in the extracellular fluid both through direct effects on bones and kidneys and indirectly (via stimulating calcitriol synthesis) on the intestinal mucosa, thereby enhancing the efficiency of Ca²⁺ absorption in the gut. By reducing renal phosphate reabsorption, parathyroid hormone helps lower phosphate concentration in the extracellular fluid.

3. Hyperparathyroidism

In primary hyperparathyroidism, the feedback mechanism suppressing parathyroid hormone secretion in response to hypercalcemia is impaired. This condition occurs with a frequency of 1:1000. Causes may include a parathyroid tumor (80%) or diffuse glandular hyperplasia, and in some cases, parathyroid carcinoma (less than 2%). Excess secretion of parathyroid hormone leads to increased mobilization of calcium and phosphates from bone tissue, enhanced calcium reabsorption, and increased renal phosphate excretion. As a result, hypercalcemia develops, which can cause decreased neuromuscular excitability and muscle hypotonia. Patients experience generalized and muscular weakness, fatigue, and pain in specific muscle groups, along with an increased risk of fractures of the spine, Femur, and forearm bones. Elevated concentrations of phosphate and calcium ions in the renal tubules can cause Kidney stones and lead to hyperphosphaturia and hypophosphatemia.

Secondary hyperparathyroidism occurs in chronic renal failure and vitamin D₃ deficiency, and is accompanied by hypocalcemia, primarily associated with impaired intestinal calcium absorption due to suppressed calcitriol synthesis by the damaged kidneys. In this case, parathyroid hormone secretion increases. However, elevated parathyroid hormone levels fail to normalize plasma calcium ion concentrations because of impaired calcitriol synthesis and reduced intestinal calcium absorption. Along with hypocalcemia, hyperphosphatemia is frequently observed. Patients develop skeletal damage (Osteoporosis) due to increased calcium mobilization from bone tissue. In some cases (with The Development of an adenoma or parathyroid hyperplasia), autonomous hypersecretion of parathyroid hormone compensates for hypocalcemia and leads to hypercalcemia (tertiary hyperparathyroidism).

4. Hypoparathyroidism

The main symptom of hypoparathyroidism, caused by parathyroid gland insufficiency, is hypocalcemia. A decrease in blood calcium ion concentrations can trigger neurological, ophthalmological, and cardiovascular disorders, as well as Connective Tissue lesions. Patients with hypoparathyroidism exhibit increased neuromuscular conductivity, episodes of tonic spasms, spasms of the Respiratory Muscles and Diaphragm, and laryngospasm.

B. Calcitriol

Like other Steroid Hormones, calcitriol is synthesized from Cholesterol.

The hormone's action aims to increase the concentration of calcium in blood plasma.

1. Structure and Synthesis of Calcitriol

In the Skin, 7-dehydrocholesterol (provitamin D₃) is converted into the immediate precursor of calcitriol—cholecalciferol (vitamin D₃). During this non-enzymatic reaction driven by UV radiation, the bond between the ninth and tenth carbon atoms in the cholesterol molecule is cleaved, ring B opens, and cholecalciferol is formed (Fig. 11-38). This is how The Human Body produces the majority of vitamin D₃, though a small amount is obtained from food and absorbed in the Small Intestine along with other Fat-soluble Vitamins.

Fig. 11-38. Scheme of calcitriol synthesis. 1 — cholesterol is the precursor of calcitriol; 2 — in the skin, 7-dehydrocholesterol is non-enzymatically converted into cholecalciferol; 3 — in the Liver, 25-hydroxylase converts cholecalciferol into calcidiol; 4 — in the kidneys, The formation of calcitriol is catalyzed by 1α-hydroxylase.

In the epidermis, cholecalciferol binds to a specific vitamin D-binding protein (transcalciferin), enters the bloodstream, and is transported to the liver, where 25-carbon hydroxylation occurs to form calcidiol [25-hydroxycholecalciferol, 25(OH)D₃]. Complexed with the vitamin D-binding protein, calcidiol is transported to the kidneys and hydroxylated at the first carbon atom to form calcitriol [1,25(OH)₂D₃]. It is 1,25(OH)₂D₃that represents the active form of vitamin D₃.

The hydroxylation taking place in the kidneys is the rate-limiting step. This reaction is catalyzed by the mitochondrial enzyme 1α-hydroxylase. Parathyroid hormone induces 1α-hydroxylase, thereby stimulating the synthesis of 1,25(OH)₂D₃. Low concentrations of phosphates and Ca²⁺ ions in the blood also accelerate calcitriol synthesis, with calcium ions acting indirectly via parathyroid hormone.

During hypercalcemia, 1α-hydroxylase activity decreases, while 24α-hydroxylase activity increases. In this case, the production of the 24,25(OH)₂D₃ metabolite rises, which may possess biological activity, though its precise role remains incompletely understood.

2. Mechanism of Calcitriol Action

Calcitriol exerts its effects on the small intestine, kidneys, and bones. Similar to other steroid hormones, calcitriol binds to an intracellular receptor in the target cell. A hormone-receptor complex is formed, which interacts with Chromatin and induces the transcription of structural genes, resulting in the synthesis of proteins that mediate the effects of calcitriol. For example, in intestinal cells, calcitriol induces the synthesis of Ca²⁺-transporting proteins that ensure the absorption of calcium and phosphate ions from the intestinal lumen into the intestinal epithelial cell and their subsequent Transport from the cell into the blood. Consequently, the concentration of calcium ions in the extracellular fluid is maintained at the level required for the mineralization of the bone organic matrix. In the kidneys, calcitriol stimulates the reabsorption of calcium and phosphate ions. A deficiency of calcitriol impairs the formation of amorphous calcium phosphate and hydroxyapatite crystals in the bone matrix, leading to Rickets and Osteomalacia. It has also been found that at low calcium ion concentrations, calcitriol promotes calcium mobilization from bone tissue.

3. Rickets

Rickets is a childhood disease associated with inadequate bone mineralization. Impaired bone mineralization is a consequence of calcium deficiency. Rickets may be caused by the following factors: dietary vitamin D₃ deficiency, impaired intestinal absorption of vitamin D₃, reduced synthesis of calcitriol precursors due to insufficient sun exposure, 1α-hydroxylase deficiency, or defects in calcitriol receptors in target cells. All these factors lead to decreased intestinal calcium absorption, lowered blood calcium concentrations, stimulation of parathyroid hormone secretion, and, consequently, the mobilization of calcium ions from bone. In rickets, the cranial bones are affected; the rib cage and Sternum protrude forward; the tubular Bones and joints of the arms and legs become deformed; the abdomen enlarges and protrudes; and motor development is delayed. The primary Methods for preventing rickets are proper Nutrition and adequate sun exposure.

C. Role of Calcitonin in Calcium Homeostasis Regulation

Calcitonin is a polypeptide consisting of 32 amino acid residues with a single disulfide bond. The hormone is secreted by parafollicular thyroid C-cells or parathyroid C-cells as a high-molecular-weight precursor protein. Calcitonin secretion increases when blood Ca²⁺ concentrations rise and decreases when Ca²⁺ concentrations fall. Calcitonin is an antagonist of parathyroid hormone. It inhibits the release of Ca²⁺ from bone by reducing osteoclast activity. Additionally, calcitriol suppresses renal tubular reabsorption of calcium ions, thereby stimulating their renal excretion in urine. The rate of calcitonin secretion in women strongly depends on estrogen levels. With estrogen deficiency, calcitonin secretion drops, accelerating calcium mobilization from bone tissue and leading to the development of osteoporosis.