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

James T. McCarthy & Rajiv Kumar Calcium Homeostasis James T. McCarthy & Rajiv Kumar

Hormonal Regulators Calcitonin (CT) Parathormone (PTH) 1,25 Vitamin D3 Lowers Ca++ in the blood Inhibits osteoclasts Parathormone (PTH) Increases Ca++ in the blood Stimulates osteoclasts 1,25 Vitamin D3 Increase Ca++ uptake from the gut

Renal tubular reabsorption of Calcium 80-85 of calcium is reabsorbed at proximal tubule and medullary loop of henle (passive transport According to physiologic needsat the DISAL tubule and adjacent cortical thick ascending limb ( where PTH, Vit D exert its effect) CCT—cortical collecting tubule; IMCD—inner medullary collecting duct or tubule; PST—proximal straight tubule.

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) 14

Increase of calcitonin hypocalciemia hypophosphatemia hyperphosphaturia Decrease of calcitonin - hypercalciemia hyperphosphatemia hypophosphaturia 15

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) 16

2 Main regulators of Calcium and phosphorus: PARATHYROID HORMONE Vitamin D 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 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: 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 by: 1. In the presenc e of permissive amounts of vitamin D it stimulates bone resorptionrelease 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) Hypofunction hypocalciemia hyperphosphatemia hypophosphaturia tetanus Hyperfunction (Recklinghausen’s disease) hypercalciemia hypophosphatemia hyperphosphaturia osteoporosis Accumulation of Са in tissues 24

Hyperparathyroidism: adenoma or hyperplasia or ectopic

Hypocalcemia

Vitamin D Metabolism

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 UV Increases Ca++ uptake from the gut Increase transcription and translation of Ca++ transport proteins in gut epithelium Minor roll: also stimulates osteoclasts Increase Ca++ resorption from the bone UV Cholesterol precursor 7-dehydrocholesterol Vitamin D3 25 Vitamin D3 1,25 Vitamin D3 -made in the liver, the skin, the liver, and the kidney Liver: cholesterol precursor transformed to 7-dehydrocholesterol Skin: UV transforms 7-dehydrocholesterol to Vit D3 Liver: Enzyme transforms Vit D3 to 25-OH-Vit D3 Kidney: Enzyme transforms 25-Vit D3 to 1,25 Vit D3 -lack of melanin pigment in Northen Europeans was thought to account for the lower light level: let more UV across the skin to ensure high enough levels of Vit. D3 -increases Ca++ uptake from the gut -made from cholesterol…….acts like a steroid…..what kind of receptors? How would they act? (they increase transcription and translation of Ca++ transport proteins in the epithelial cells of the gut) -minor roll: also acts to stimulate osteoclasts, (which would do what?) increasing Ca++ resorption from the bone -control of secretion: -low Ca++ levels causes increase of PTH, which increases enzymes in the kidney (more enzyme, more 1,25 Vit. D3) 1,25 Vitamin D3 Low plasma Ca++ increase kidney enzymes

Images of Rickets Wrist expansion: cupping and fraying of hypertrophied metaphyseal plate Rachitic Rosary Bone demineralization and deformity Rotten-stump epiphysis