Hormonal control of calcium homeostasis

• Calcium homeostasis


  Complex equilibrium between bone formation/resorption, calcium absorption/secretion from kidneys and GI
• Osteoblasts


  • Derive from fibroblasts, build the bone matrix, converted into osteocytes
• Osteoclasts


  • Derive from macrophages, "bone-destroying cells", population controlled by estrogen/androgen
• PTH (parathyroid hormone)


  Stimulates osteolysis
• Calcitriol (vitamin D derivative)


  Essential for bone mineralisation, stimulates calcium absorption in the intestine
• Oestrogens/androgens


  Maintenance of bone integrity
• Calcium homeostasis depends on three organ systems

  • Skeleton
  • Kidneys
  • Intestinal tract
• Calcium participates in neuromuscular excitability, myocontraction, nerve transmission, coagulation of blood or milk, as a second messenger to initiate biological process, essential for various enzymatic activity, modulates viscosity in the intracellular medium, essential for the process of exocytosis, cell-cell interaction, cell duplication, involved in the process of apoptosis, essential element of bones, teeth, cartilage
• 98.9% of total body calcium stored in the bones, 0.1% in extracellular fluid, 1% in the cells, mainly stored in SER, but only trace of free calcium present in intracellular medium
• Resting intracellular cytosolic concentration of calcium 100 nM, approximately 0.2 g, can increase transiently by 10–100-fold to initiate a biological process, stored in intracellular organels (mainly sarcoplasmic reticulum): 9 g
• Extracellular concentration of calcium: approximately 1 mM, Total plasma levels: 2.15-2.6 mM (8.6-10.6 mg/dl), Ratio Ca++ intra/extra-cellular: ≈ 1/10,000, Concentration in blood must be tightly maintained (hypocalcaemia cause dangerous activation of neurones in CNS and PNS (tetany)
• Calcium sources and excretion

  • Dietary intake 1,000 mg
  • Fecal excretion 800 mg
  • Rapid exchangeable pool (bone surface) 4,000 mg
  • Bone calcium reserve 1,000,000 mg
  • Extracellular fluid 1,000 mg
  • Kidneys 500 mg
  • Plasma 500 mg
• Bone mass: 80% consists of cortical bones (major outer part of longitudinal bones), 20% of trabecular bones, or spongy bone (major inner part of vertebras, ribs, and skull), 15% of our total bone mass normally turnovers each year
• Osteogenesis


  Recruitment of osteoblasts from precursors, synthesis and extrusion of bone collagen, osteonectin, osteocalcin and fibrinonectin to form organic matrix, mineralisation with calcium phosphate crystals, conversion of osteoblasts to osteocytes
• Osteolysis


  Recruitment of osteoclasts by cytokines, adhesion to bone matrix and proteolysis of collagen, release of IGF which activates osteoblasts
• Continuous physiological stress


  Stimulates osteoblastic deposition and calcification
• Remodelling starts with release of IL-6 from osteoblasts


  Stimulates osteoclasts, osteoclasts resorb bone which liberates IGF-1 to stimulate osteoblasts
• Vitamin D


  Family of sterols, main source 7-dehydrocholesterol synthesised in skin, converted to active form calcitriol in liver and kidney
• Calcitriol (vitamin D hormone)


  Binds to cytoplasmic receptors that migrate to nucleus, activates or suppresses transcription of target genes, activates calcium binding protein in intestine, critical for bone mineralisation, increases calcium reabsorption in kidneys
• Parathyroid hormone (PTH)


  84 aa peptide secreted by parathyroid glands, stimulates bone resorption, increases calcium reabsorption in kidneys, stimulates calcitriol synthesis
• Calcitonin


  32 aa peptide made in thyroid, decreases calcium levels by inhibiting osteoclast activity
• Oestrogens/androgens


  Oppose bone resorption, inhibit osteoclast recruitment and cause osteoclast apoptosis
• Glucocorticoids


  Low doses required for osteoblast differentiation, excessive inhibits bone formation
• Osteoporosis: reduction of bone mass with distortion of the microarchitecture, imbalance between bone formation and resorption, affects postmenopausal women and elderly
• Paget's disease: abnormal synchronisation of osteolytic/osteoblastic phases, characterised by gross deformity of bones
• Rickets (children): bone weakness and deformities due to vitamin D deficiency
• Osteomalacia (adults): bone weakness and deformities due to defect in intestinal calcium absorption
• Achondroplasia: most common form of dwarfism, involves conversion of cartilage to bone, usually with normal trunk and head but very short extremities, due to mutation in growth factor receptor FGFR3