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Hormonal regulation of calcium and phosphorus homeostasis. Calcium • Regulate neuromuscular excitability • Blood coagulation • Secretory processes • Membrane integrity • Plasma membrane transport • Enzyme reactions • Release of hormones and neurotransmitters • Bone mineralization Phosphorus • Important role in cellular metabolism • source of of energy in cellular reactions • Component of phospholipids in membranes Calcium Homeostasis James T. McCarthy & Rajiv Kumar Hormonal Regulators • Calcitonin (CT) – Lowers Ca++ in the blood – Inhibits osteoclasts • Parathormone (PTH) – Increases Ca++ in the blood – Stimulates osteoclasts • 1,25 Vitamin D3 – Increases Ca++ in the blood – Increase Ca++ uptake from the gut – Stimulates osteoclasts Renal tubular reabsorption of Calcium CCT—cortical collecting tubule; IMCD—inner medullary collecting duct or tubule; PST—proximal straight tubule. 80-85 of calcium is reabsorbed at proximal tubule and medullary loop of henle (passive transport According to physiologic needsat the DISAL tubule and adjacent cortical thick ascending limb ( where PTH, Vit D exert its effect) Renal tubular reabsorption of phosphorus Most of the inorganic phosphorus in serum is ultrafilterable at the level of the glomerulus. CCT—cortical collecting tubule; IMCD—inner medullary collecting duct or tubule; PST—proximal straight tubule. MAINTENANCE OF CALCIUM AND PHOSPHATE HOMEOSTASIS • It is dependent on – Intestinal – Bone – Renal function MAINTENANCE OF CALCIUM AND PHOSPHATE HOMEOSTASIS • It is dependent on – Intestinal – Bone – Renal function Na Cl and KCL complete absorbtion at intestine but CALCIUM AND PHOSPHATE is incomplete * because of the requirement for vitamin D and formation of insoluble salts like; Calcium phosphate,calcium oxalate and magnesium phosphate at the intestinal lumen Calcitonin Is synthesized by parafollicular cells of thyroid gland - Affects the metabolism of Са and Р Promotes the transferring of Са2+ from blood into bones Inhibits reabsorption of Р in kidneys (decreases the content of Р in blood due to its excretion with urine) - Increase of calcitonin hypocalciemia hypophosphatemia hyperphosphaturia Decrease of calcitonin - hypercalciemia - hyperphosphatemia - hypophosphaturia PARATHYROID GLANDS Parathyroid hormone - protein - - Affects the metabolism of Са and Р Promotes moving of Са2+ from bones into blood Inhibits reabsorption of Р in kidneys (decreases the content of Р in blood due to its excretion with urine) Stimulates the absorption of Ca in the intestine Дія зв’язана з вітаміном D (утворює активну форму вітаміну D в нирках) 2 Main regulators of Calcium and phosphorus: PARATHYROID HORMONE 1. PTH ( Parathyroid hormone) 84 amino peptide Molecular mass if 9.5 kilodalton no carbohydrate or other covalently bound molecules Full biologic activity resides in the amino terminal third of the molecule PTH 1-34 has full biologic activity while region 25-34 is for receptor binding Vitamin D • Is a fat soluble steroid • That is present in the diet and can be synthesized from the skin PARATHYROID HORMONE • A polypeptide secreted from the parathyroid glands in response to a decrease in the plasma concentration of ionized calcium Parathyroid Hormone Precursor of PTH are: A. PreproPTH differs from proPTH by having additional 25 amino acid amino terminal * it is the hydrophobic end • *at Rough endoplasmic reticulum Parathyroid Hormone • Precursor of PTH are: B. ProPTH differs from native hormone by having an amino terminal highly basic hexapeptide extension * it is hydrophobic end * at PTH golgi apparatus PTH increases Ca concentration • 1. In the presenc e ofby: permissive amounts of vitamin D it stimulates bone resorptionrelease of calcium phosphates • 2. Enhances intestinal Calcium and phosphate absorption promotes formation of vit D • 3. It augments renal calcium reabsorption PTH • Regulation of Synthesis – Biosynthesis is regulated by levels of calcium – An acute decrease of Ca results in marked increase of PTH mRNA increase of PTH synthesis – Effects is at the level of gene transciption, MRNA stability, mRNA translation – Rate of degradation of PTH is low if low calcium and high if calcium is high – 1, 25 (OH)2D3 receptor complex binds with vitamin D in the promoter region of PTH gene and inhibits transcription decreases the production of PTH – PTH synthesis can be enhanced by the size and number of PTH producing chief cells in cases of prolonged hypocalcemia - Hyperfunction (Recklinghausen’s disease) hypercalciemia hypophosphatemia hyperphosphaturia osteoporosis Accumulation of Са in tissues - Hypofunction hypocalciemia hyperphosphatemia hypophosphaturia tetanus Hyperparathyroidism: adenoma or hyperplasia or ectopic Hypocalcemia Regulation of Metabolism and synthesis of 1,25()H)2-D3 Primary Regulators Secondary Regulators Hypocalcemia (↑) PTH(↑) Hypophosphatemia(↑) Calcitriol (↓) Estrogen Androgens Progesterone Insulin Growth Hormone Prolactin Thyroid Hormone 1,25 Vitamin D3 • Increases Ca++ uptake from the gut – Increase transcription and translation of Ca++ transport proteins in gut epithelium • Minor roll: also stimulates osteoclasts UV – Increase Ca++ resorption from the bone Cholesterol precursor 7-dehydrocholesterol Vitamin D3 25 Vitamin D3 1,25 Vitamin D3 Low plasma Ca++ increase kidney enzymes Images of Rickets Wrist expansion: cupping and fraying of hypertrophied metaphyseal plate Bone demineralization and deformity Rachitic Rosary Rotten-stump epiphysis