unit 5, lesson 4, Hormonal Regulation of Calcium Metabolism

• The lecture covers the hormonal regulation of calcium metabolism
• The learning outcomes are to understand the importance of calcium homeostasis and how it is maintained, along with the physiological actions of the hormones involved

Hormones Involved

• Parathyroid hormone (PTH) raises plasma calcium levels
• Calcitonin (CT) decreases plasma calcium levels
• Vitamin D (Vit D) raises plasma calcium levels
• Other hormones in calcium homeostasis include oestrogens, growth hormone, and glucocorticoids

Calcium Homeostasis

• Dietary intake of 1000mg of calcium contributes to the plasma calcium level of 2.2 - 2.6mM
• Absorption of 350mg occurs in the gut, with 150mg secreted
• Faecal excretion accounts for 800mg
• Bone formation uses 500mg of calcium, balanced by bone resorption of 500mg
• Storage of calcium in bone is approximately 1kg
• PTH and Vitamin D increase reabsorption, while calcitonin decreases it
• Urinary excretion removes 200mg of calcium
• PTH and Vitamin D increase filtration, while calcitonin decreases it

Calcium Importance

• Calcium is essential for bone and teeth formation
• Calcium is essential for normal skeletal and smooth muscle function
• Calcium is essential for cellular division, adhesion, growth, blood coagulation and enzyme activity
• Calcium maintains activity of excitable tissues such as neuromuscular transmission, cellular hormone release, and heart function

Calcium Location and Concentration

• Over 95% of calcium is stored in bone
• About 1% of calcium is intracellular
• Extracellular plasma calcium concentration is 2.2-2.6mM
• Cytosolic intracellular calcium concentration is 10-100nM

Chemical Form

• 50% of calcium is free (active form)
• 45% is protein-bound (albumin & globulins)
• 5% is complexed with anions like bicarbonate, sulphate, citrate, and phosphate
• The ratio is influenced by plasma pH

Sources of Calcium

• Tofu
• Dairy products
• Bread
• Vegetables like curly kale, okra, horseradish, watercress, peas, broccoli, cabbage, celery, and parsnips
• Pulses like red kidney beans, soya bean, and soya products
• Cereals enriched with calcium
• Dried fruit like figs
• Nuts

Phosphate

• Phosphate metabolism is closely linked to calcium but less controlled
• Phosphate is essential for synthesizing DNA, RNA, ATP, membrane phospholipids, and bone
• Normal plasma phosphate range is 0.8-1.5mM

Parathyroid Hormone (PTH)

• Parathyroid glands consist of 4 oval, pea-sized bodies embedded in the back of the thyroid gland, found in all terrestrial vertebrates
• There are two types of epithelial cells in the parathyroid glands surrounded by connective tissue where chief cells are small, numerous, with clear cytoplasm and dense granules, and secrete PTH, and oxyphil cells are larger, fewer, with less granular cytoplasm and unknown function

PTH Production

• PTH is an 84 amino acid peptide derived from a larger precursor
• Rapid cleavage occurs after release in the liver and kidney, with a plasma half-life of 2-5 minutes
• The active portion consists of the 34 N-terminal amino acids
• Some cleavage occurs with in parathyroid glands

Control of Release of PTH

• Secretion is controlled by free ionised calcium concentration in plasma
• Low calcium concentration directly stimulates PTH release, involving a G protein-coupled cell surface calcium sensing receptor, with receptors found in all tissues
• Receptors have low affinity for Calcium²⁺ with an EC₅₀ of 3mM
• Magnesium has similar, but weaker, effects, with unclear physiological role
• Plasma phosphate levels have no direct effect
• Active Vitamin D metabolite, calcitriol, reduces PTH production

Physiological Actions of PTH

• PTH raises plasma free ionised Calcium²⁺ concentration
• There is interaction with active form of Vitamin D₃, calcitriol on the kidney, causing a rapid increase in distal tubule Calcium²⁺ reabsorption from glomerular filtrate and decreased phosphate reabsorption
• Plasma Calcium²⁺ and Magnesium²⁺ increases
• Plasma phosphate decreases
• PTH promotes formation of active vitamin D metabolite, calcitriol, in kidney tubular cells

Bone

• PTH stimulates rapid efflux of Calcium²⁺ across 'osteocyte-osteoblast bone membrane' into extracellular fluid
• PTH indirectly stimulates osteoclasts to release Calcium²⁺ and phosphate by bone resorption
• PTH increases number of osteoclasts involved

GI Tract

• PTH indirectly stimulates intestinal absorption of Calcium²⁺ and phosphate
• The effect is mediated by increased synthesis of calcitriol by kidney and takes at least 24 hours to occur

Calcitonin

• Calcitonin is a 32 amino acid peptide secreted by exocytosis from C cells of the thyroid gland
• This entire peptide is required for biological activity and has high species divergence
• Calcitonin stimulates specific plasma membrane receptors
• PTH is more vital when controlling Calcium²⁺ levels in Humans

Control of Release

• Secretion is controlled by free ionised Calcium²⁺ concentration in plasma
• High Calcium²⁺ concentration directly stimulates calcitonin release
• Gastrin releases calcitonin
• It prevents hypercalcaemia after meals and acts as a satiety hormone
• The plasma t₁ of calcitonin is 2-15 minutes and it is degraded in plasma and kidney

Physiological Actions

• Calcitonin decreases plasma free ionised Calcium²⁺ concentration
• It has a lowered effect of plasma Calcium²⁺, which increases PTH secretion and production of vitamin D metabolites

Bone

• Calcitonin decreases Calcium²⁺ efflux across osteocyte-osteoblast bone membrane
• It directly reduces osteoclast activity to resorb bone
• Calcitonin decreases formation of new osteoclasts from bone marrow

Kidney

• Calcitonin inhibits reabsorption of Calcium²⁺ and phosphate from loop of Henle and distal tubule
• It has an increased excretion of Calcium²⁺, Na⁺, K⁺, and decreased excretion of Mg²⁺

Vitamin D

• Vitamin D consists of essential fat-soluble sterols that can be classified as a hormone
• Vitamin D is obtained from diet or synthesised in the skin following sunlight (U.V.) exposure
• It is metabolised to produce active metabolite, calcitriol
• Vitamin D has the most important effects on bone, kidney and Gl tract
• Many additional target organs and it stimulates cell differentiation, and inhibits proliferation of skin and immune cells
• Vitamin D modulates seasonal and daily biorhythms

Metabolism of Vitamin D

• Inactive liver precursor, 7-dehydrocholesterol, is converted to cholecalciferol by U.V. light or photo-isomerisation in skin
• Vitamin D is obtained from diet or fish liver oils, sardines, herring, salmon, tuna, liver, eggs, cereals, margarine and some dairy products as it is often fortified with vitamin D
• The recommended dietary allowances for Vitamin D in U.K. 200IU micrograms
• Vitamin D is hydroxylated first in the liver to 25-hydroxy-cholecalciferol (25-(OH)D₃)
• Vitamin D is hydroxylated secondly in the kidney to the active form: alpha,25-dihydroxycholecalciferol (calcitriol, 1,25-(OH)₂D₃), or in skin
• Ergocalciferol is derived from plant sterol ergosterol and is hydroxylated similarly to produce alpha, 25-dihydroxycalciferol (calciferol, 1,25-(OH)₂D₂)

Transport and Control of Release

• Calcitriol is transported in blood bound to vitamin D-binding alpha-globulin or transcalciferin in the unbound form, which makes it active
• The plasma t₁₂ transport time is 3-6 hours
• 10 micrograms a day is needed to maintain Calcium²⁺ homeostasis
• PTH promotes 1alpha-hydroxylation to active metabolite and inhibits 24-hydroxylation to weakly active metabolite
• Calcitriol regulates its own synthesis by stimulating 24-hydroxylation and by negative feedback to inhibit 1alpha-hydroxylase with 1alpha-hydroxylase that is also stimulated by decreased phosphate

Mechanism of Action of Calcitriol

• Free calcitriol and calciferol are lipophilic and cross the plasma membrane
• Calcitriol binds to vitamin D receptors (VDR) in the nucleus VDR heterodimerises with the Retinoid X receptor (RXR) which either undergoes stimulation or inhibition of target genes
• The effects take several days to appear following the synthesis of cytosolic calcium binding proteins, calbindins (CaBP(9K) and CaBP(28K)), transporter pump protein (Ca-Mg-ATPase), osteocalcin
• Several VDR exist, with different distributions, and may be involved in genetic susceptibility to osteoporosis and colon cancer
• Calcitriol binds to membrane-associated receptors to increase intestinal Calcium²⁺ absorption

Cellular events

• Calcitriol helps open chloride channels, activate protein kinase C (PKC) and mitogen-activated protein (MAP) kinases

Physiological Actions of Calcitriol

• Raises plasma free ionised Calcium²⁺ concentration

GI tract

• Calcitriol promotes active absorption of Calcium²⁺ in the upper small intestine

Kidney

• Calcitriol promotes active absorption of Calcium²⁺, which is less important, and increases phosphate excretion

Bone

• Calcitriol promotes active resorption of Calcium²⁺ and increases phosphate absorption
• It indirectly activates osteoclasts and increases activity and potentiates effects of PTH

Clinical Disorder Associated with Calcitriol

• Vitamin D deficiency can cause Rickets in young children and osteomalacia (soft bones) in adults
• Vitamin D deficiency is most common in the Middle and Far East
• Causes are genetic, intestinal fat malabsorption, chronic liver disease, lack of sunlight, or dietary deficiencies
• Children express swollen growing ends of bone, bone bent and deformed, and 'bowed legs' as a result
• Adults express bone pain, partial fractures and muscle weakness
• Treatment includes Vitamin D analogues and Calcium²⁺ supplements

Regulation Steps

• A fall in the plasma Calcium concentration causes secretion of PTH from parathyroids
• Secretion of PTH from parathyroids causes mobilisation of Calcium from bone and conversion of 25-(OH)-D₃ to calcitriol
• Mobilisation of Calcium from bone causes a rise in the plasma Calcium concentration
• Conversion of 25-(OH)-D₃ to calcitriol causes increased Calcium absorption in the GI tract and decreased excretion of Calcium by the kidney
• Increased Calcium absorption in the GI tract and decreases excretion of Calcium by the kidney causes a rise in the plasma Calcium concentration