Calcium Homeostasis - Part 1

Calcium Homeostasis - Part 1

• Calcium (and phosphate) play a significant role in skeletal and tooth formation, as well as regulating biochemical pathways and signaling cascades, and are a component of connective tissue.
• Calcium is involved in skeletal rigidity via hydroxyapatite and calcium phosphate, intrinsic/extrinsic blood clotting (haemostasis), smooth and striated muscle excitation/contraction coupling, acetylcholine in neuromuscular junction, and cell-to-cell adhesion.
• Calcium is also a second messenger for enzymatic activity, with calmodulin as an example.
• Ionized calcium is biologically active, while protein-bound calcium is inactive and not excreted.
• Plasma ionised calcium (Ca²⁺) is 2.1-2.8 mmol/l and ~50% in free form.
• Plasma inorganic phosphate (Pi) concentration is 0.8-1.5 mmol/l, and ~84% is in the protein-bound inactive form.
• Dietary calcium, resorbed calcium from bone, and calcium lost via faeces/sweat/saliva must balance with calcium deposited in bone to maintain homeostasis.

Learning Outcomes

• Describe biological functions of Ca²⁺.
• Identify hormones that regulate extracellular Ca²⁺ levels, understand their mode of action, sites of hormone production.
• Describe symptoms and signs of hypercalcaemia and hypocalcaemia.
• List causes for hypercalcaemia and hypocalcaemia(disorders).
• Describe parathyroid hormone (PTH) synthesis and the role of Ca²⁺ sensing receptors.
• Describe how PTH exerts its effects on its target cells—list these effects.
• Describe symptoms and signs of hyperparathyroidism & hypoparathyroidism.
• Describe how calcitonin effects target cells—list these effects.
• Explain vitamin D metabolism regulation and its effect on target cells.
• Explain how PTHrP, FGF23, gonadal and steroid hormones affect calcium/phosphate metabolism.

Recommended Reading

• Medical Physiology, 3rd Edition, Elsevier, Chapter 52 (pages 1054-1069)
• Leach et al. (2020), International Union of Basic and Clinical Pharmacology, CVIII., Calcium-Sensing Receptor Nomenclature, Pharmacology, and Function, Pharmacological Reviews, 72, 558-604. [link]
• Khosla, S., and Munroe, D.G. (2017), Regulation of bone metabolism by sex steroids, Cold Spring Harbor Perspectives in Medicine, 8. [link]

Inorganic Phosphate (Pi)

• Inorganic phosphate plays a role in bone formation by forming crystals with calcium (hydroxyapatite).
• Pi is a component of nucleotides, nucleosides and phospholipids, and it affects cellular signaling by phosphorylating proteins and is part of second messenger systems.
• Normal plasma inorganic phosphate concentration is 2.3 mmol/L.

Calcium Homeostasis

• Achieved by the actions of three hormones acting on bone, kidneys and intestines: Vitamin D, PTH and calcitonin.
• Vitamin D is crucial for calcium homeostasis and is converted into active form 1,25-dihydroxyvitamin D in the kidneys

Parathyroid Hormone (PTH)

• Produced in the parathyroid glands.
• PTH is important for calcium homeostasis by influencing bone, the GI tract and kidneys.
• PTH regulates calcium reabsorption in the kidneys.
• PTH increases calcium absorption by stimulating 1,25-dihydroxyvitamin D production in the kidney.
• PTH stimulates bone resorption resulting in calcium release.

Calcium-Sensing Receptors (CaSR)

• Free calcium is "sensed" by CaSR.
• Heterozygous CaSR inactivation mutations lead to failure of PTH inhibition at high calcium levels.
• These mutations cause Familial hypercalcemic hypocalciuria (FHH).

Vitamin D

• Vitamin D (cholecalciferol) is a prohormone.
• It is converted into its active form (1,25-dihydroxyvitamin D, calcitriol) by hydroxylation in the liver and kidneys.
• Regulation of the second hydroxylation involves growth hormone, prolactin, oestrogen, FGF23.
• 1,25-dihydroxyvitamin D affects the small intestine, increasing calcium transport.

Metabolites of vitamin D

• The primary role of 1,25-dihydroxyvitamin D is to contribute to calcium homeostasis in small intestine and kidneys.
• Vitamin D receptor (VDR) influences gene expression, affecting calcium transport in enterocytes.
• Na+-Pi cotransporter activity influenced by 1,25-dihydroxyvitamin D enhances calcium reabsorption.
• Osteoclast numbers increase in response to 1,25-dihydroxyvitamin D.

Calcitonin

• Produced by thyroid gland clear cells.
• Plays a role in responding to hypercalcaemia.
• Has antagonistic action to PTH in bone.

Other Hormones Involved in Calcium Homeostasis

• Sex hormones (e.g., estrogen, testosterone) influence bone turnover and density.
• Glucocorticoids affect bone density and calcium absorption.
• Parathyroid hormone-related protein (PTHrP) mimics PTH's action on bones and kidneys.
• Regulation and influences of bone turnover by these other hormones

Inorganic Phosphate Homeostasis

• Phosphate homeostasis depends on factors like PTH, calcitriol, and FGF23 (fibroblast growth factor 23).
• FGF23 is secreted by osteocytes and is regulated by blood phosphate levels.
• FGF23 causes increased phosphate excretion in the urine.
• PTH and calcitriol lead to phosphate release from bone.

Hypocalcaemia

• Low plasma Ca²⁺ levels. Symptoms include pins and needles, muscle spasms (tetany), paralysis, and convulsions.

Hypercalcaemia

• High plasma Ca²⁺ levels. Symptoms include lethargy, depression, constipation, kidney stones, frequent urination, nausea, and cardiac arrhythmias.

Hypoparathyroidism

• Lack of PTH due to production issues or responsiveness defects in target tissues.
• Results in hypocalcaemia and hyperphosphataemia (high inorganic phosphate in blood).

Hyperparathyroidism

• Excess PTH production, either primary (tumors) or secondary (chronic kidney disease, calcium malabsorption).
• Leads to hypercalcaemia. Symptoms include hypertension, constipation, weakness, confusion.

Too little Vitamin D

• Deficiency outcomes include increased PTH levels, high bone turnover, reduced bone density, increased risk of hip fracture. In severe cases, osteomalacia (adults) or rickets (children) develop

Summary

• Calcium exists in a homeostatic balance between bound (hydroxyapatite, calcium phosphate), and free (ionized) forms.
• Key regulators of calcium homeostasis include vitamin D metabolites, parathyroid hormone (PTH), and calcitonin.

Explore the intricacies of calcium and phosphate roles in the body. This quiz covers their importance in skeletal formation, biochemical pathways, and muscle function. Test your knowledge on calcium balance in various bodily processes and its biological significance.