Parathyroid

• Calcium


  • Major component of bone (~50% bone weight as hydroxyapatite)
  • 99% of Ca2+ in bone & teeth mineral
  • Intracellular second messenger (e.g. muscle contraction)
  • Needed for blood clotting
  • Extracellular [Ca2+] carefully regulated (Normal: 2.2 - 2.55 mM)
  • Ca2+ exists in 3 forms - bound to albumin, citrate complex, free Ca2+ ion
• Calcium as second messenger

  • Ca2+ necessary for heart contraction
  • Intracellular Ca2+ triggers muscle contraction
  • Ca2+ activates contractile proteins and SR regulates intracellular Ca2+
  • Calmodulin - ubiquitous Ca2+-sensing protein
• Cytosolic calcium changes in signalling

  Increase in cytosolic causes: Fast signals - muscle contraction, Sustained signals - transmitter secretion, Long-term changes - gene expression
• Intracellular Ca2+ storage


  • Stored in endoplasmic reticulum, in muscle: sarcoplasmic reticulum (SR)
  • Ca2+ signalling is compartmentalised
  • Signal varies due to amplitude, frequency shape
• Calcium signalling in disease

  • Ca2+ overload inside cell - toxic (muscle contractile dysfunction, neurodegenerative processes)
  • Hypercalcaemia - cardiac arrhythmia, lower neuromuscular transmission
  • Hypocalcaemia - tetany, epilepsy, blood clotting problems
• Osteoblasts


  • Bone forming cells, secrete osteoid (forms bone matrix), begin mineralisation
• Osteocytes


  • Mature osteoblasts, no longer secrete matrix but surrounded by it, maintain metabolism and participate in nutrient/waste exchange
• Osteoclasts


  • Function in resorption and degradation of existing bone, regulate Ca2+ release from bone
  • Release H+ ions (proton pumps) into resorptive cavity to acidify and dissolve mineralised bone matrix
  • Release Ca2+, H3PO4, H2CO3, water
  • Release hydrolytic enzymes (e.g. cathepsins, MMPs) to digest organic components of matrix
• Osteoporosis


  • Disease of bone growth & calcium metabolism, bone resorption exceeds deposition
  • Factors: inadequate Ca2+ intake, genes, hormones, smoking
  • Treatment: bisphosphonates - inhibit activation of enzymes that utilise pyrophosphate
• Parathyroid gland


  • 4 parathyroid glands, posterior to thyroid, embedded in its lobes
  • Chief cells - site of synthesis & secretion of parathyroid hormone (PTH)
  • Oxyphil cells - appear at puberty, larger size and smaller nucleus vs chief cells
• Parathyroid - biosynthesis, storage & secretion

  1. Synthesised as preprohormone by parathyroid gland chief cells

  2. Active form (84 aa peptide) cleaved from preprohormone before release

  3. Released by exocytosis in response to reduced plasma Ca2+

  4. Synthesised continuously, degraded if not released

  5. Secretion controlled by Vitamin D (-ve feedback)
• Biological activity of parathyroid

  • Increase plasma Ca2+ levels & Decrease plasma phosphate levels
  • Increases number and activity of osteoclasts, stimulates bone resorption
  • Causes Ca2+ reabsorption & phosphate excretion in kidney
  • Stimulate vitamin D3 synthesis to increase Ca2+ reabsorption in intestine
• Calcium regulation of parathyroid release

  • Ca2+ is dominant regulator, continuous secretion - rapid clearance (5 min)
  • Maximum secretion at plasma Ca2+ <3.5 mg/dL, inversely related to [Ca2+]
  • Parathyroid gland chief cell Ca2+ receptor senses changes in extracellular [Ca2+]
  • Blood Ca2+ level (hyper- & hypocalcaemia) directly controls secretion of both calcitonin and parathyroid via negative feedback
• Hyperparathyroidism


  • Due to excess PTH secreted from benign tumour or hyperplasia of all 4 glands
  • Calcium homeostatic loss due to excessive PTH secretion, hypercalcaemia results
  • Pathophysiology related to both PTH excess and concomitant excessive production of 1,25-(OH)2D
  • Treatment: rehydration, i.v. bisphosphonates, calcitonin (moderate cases), treat underlying cause
• Primary hyperparathyroidism


  • One of most common endocrine disorders, important cause of hypercalcaemia
  • Usually from sporadic (nonfamilial) solitary parathyroid adenoma
  • Parathyroid increases blood Ca2+ levels, acts on bone, kidneys, small intestines
  • Bone "sacrificed" for this - demineralisation, bone cysts, phalangeal erosion
  • Surgical excision - >90% cure
• Hypoparathyroidism


  • Far less common, causes hypocalcaemia and hyperphosphataemia - tetany, mental, eye
  • Treatment: Ca2+, Vit D (i.v. and oral), treat underlying cause
• Types of hypoparathyroidism


  • PTH-deficient - reduced or absent PTH synthesis
  • PTH-ineffective - synthesis of biologically inactive PTH
  • PTH-resistant (pseudohypoparathyroidism) - congenital defect in PTH GPCR signalling, lack of normal response to administered PTH
• Vitamin D synthesis


  • Obtained from sun (UV on skin), food, supplements
  • Made from cholesterol, precursor biologically inert, must undergo two hydroxylation reactions in liver & kidney (stimulated by PTH) to be activated
  • Ergocalciferol = vit D2; cholecalciferol = vit D3
  • Calcitriol = 1,25-hydroxycholecalciferol = 1,25-OH vit D3 - ACTIVE form
  • Alfacalcidol (analogue) = 1α-hydroxycholecalciferol = 1α-OH-vit D3
• Vitamin D3


  • Carried by vitamin D-binding protein (VDBP)
  • Binds to Vitamin D receptor (nuclear)
  • Vitamin D3 deficiency commonest cause of hypocalcaemia
  • Regulates genes that facilitate several important body functions: stimulates intestinal calcium uptake, increases bone mineralisation, increases kidney phosphate uptake, regulates thyroid and parathyroid function, modulates neuromuscular and immune function, reduces inflammation
• Calcitonin


  • 32-amino acid linear polypeptide hormone
  • Synthesised and secreted by the parafollicular ("C") cells of the thyroid
  • Acts to decrease plasma Ca2+ levels while PTH and vitamin D act to increase plasma Ca2+ - is a physiological antagonist to PTH
  • Target cell is the bone osteoclast, inhibits osteoclast motility and cell shape
  • Calcitonin effect: rapid fall in Ca2+ caused by inhibition of bone resorption
  • Used clinically in treatment of hypercalcaemia (Salcatonin) & certain bone diseases (e.g. Paget's disease)
  • Calcitonin role in normal Ca2+ control is outweighed by PTH and Vitamin D3