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• Parafollicular (clear, C) cells

  Cells of the thyroid gland

  
• Regulation of calcitonin secretion

  1. Role of plasma Ca+2 level

  2. Role of other hormones

  
• Secretion of calcitonin is increased when plasma Ca+2 is high (~ 9.5mg/dL). Above that the calcitonin plasma level is proportional to plasma Ca+2 level.

  
• Hormones that stimulate calcitonin secretion


  • β-adrenergic agonists
  • Dopamine
  • Estrogen
  • Gastrin (the most potent stimulus)
  • CCK
  • Secretin

  
• Physiological levels of gastrin after eating do not stimulate secretion of calcitonin (because dietary Ca+2 in the intestine do not absorb yet)
• Supraphysiological doses of gastrin stimulate calcitonin releases.

  
• In Zollinger-Ellison syndrome (Gastrinoma or G cell hyperplasia or tumor) and in In pernicious anemia (associate with G cell hyperplasia), the high gastrin causes elevated plasma calcitonin level.

  
• Half-life of calcitonin


  10min (short-lived actions)

  
• Calcitonin receptors


  CPCR in the bones and kidney

  
• Effects of calcitonin


  • In bones: Inhibits bone resorption (directly inhibits osteoclast activity)
  • In kidney: Increases Ca+2 excretion in urine

  
• Physiological role of calcitonin is uncertain

  
• After thyroidectomy the bone density and plasma Ca+2 are normal as long as parathyroid glands are intact (present)

  
• After thyroidectomy when a Ca+2 load is injected there are ONLY transient abnormalities in Ca+2 hemostasis because calcitonin my be secreted from tissues other than the thyroid

  
• Role of calcitonin in young individuals and pregnant


  • Play a role in skeletal development
  • Protect the bones of the mother from excess Ca+2 loss during pregnancy (decrease bone resorption)

  
• In pregnancy, fetal bone formation & milk production are major drains on Ca+2 stores (bone resorption). Plasma conc. of 1,25-(OH)2D3 also increased. These causes bone loss in the mother if bone resorption is not simultaneously inhibited by an increase in plasma calcitonin level

  
• Summary of calcium homeostatic mechanisms

  • PTH increases plasma Ca+2 by mobilizing this ion from bone. It increases Ca+2 reabsorption in the kidney, but this may be offset by the increase in filtered Ca+2 . It also increases the formation of 1,25- dihydroxycholecalciferol.
  • 1,25-Dihydroxycholecalciferol increases Ca+2 absorption from the intestine and increases Ca2+ reabsorption in the kidneys.
  • Calcitonin inhibits bone resorption and increases the amount of Ca+2 in the urine

  
• Bone tissue


  • Organic matter: Connective tissue (matrix, collagen, osteoblasts)
  • Inorganic matter: hydroxyapatite salts (Ca10(PO4)6(OH)2

  
• Functions of bone


  • Involved in Ca+2 and phosphate hemostasis
  • Protects vital organs
  • Permits locomotion
  • Support load on gravity

  
• Bone remodeling


  1. Old bone is constantly being resorbed and new bone formed

  2. Allows bone to respond to the stress and strains that are put upon it

  
• Bone vascularity


  • Well vascularized and total blood flow ~ 200-400ml/min in adult human

  
• Bone formation during fetal development

  1. Enchondral bone formation: Bones are initially cartilaginous (most bones) then transformed into bone by ossification (Occurs during fetal development)

  2. Intramembranous bone formation: Bones are formed directly by mesenchymal cells (clavicles, mandible and certain bones of the skull)

  
• Bone growth during growth

  1. The epiphyseal plate composes of actively proliferating cartilage (formed by chondrocytes)

  2. As it lays down new bone on the end of the shaft, the bone increase in length (linear growth)

  3. Its width is proportional to the rate of bone growth

  4. Its width is affected by the number of hormones, but most markedly the GH and GF-I

  5. Bone growth ceases after epiphysial closure (the epiphysis unite with the shaft)

  
• Epiphysial closure


  1. The chondrocytes stop proliferating, become hypertrophic and secrete VEGF that leads vascularization and ossification

  2. The age at which the closure occurs is unknown

  3. The closure in various bones occurs in an orderly temporal sequence

  4. The last closing occurs after puberty

  5. Radiography can determine which epiphyses are open and which are closed

  
• Periosteum membrane


  • Outer layer of collagenous tissue
  • Inner layer of fine elastic fibers
  • Cells within the inner layer (contribute to bone growth)
  • Covers all surfaces of the bones (EXCEPT for those capped with cartilage (at the joints) and serve as site of attachment of ligaments and tendons
  • As one ages, the membrane becomes thinner and loses some of its vasculature (rendering the bones more susceptible to injury and disease)

  
• Osteoblasts

  • They are modified fibroblasts
  • Develop early from mesenchyme in the same way as fibroblasts but with extensive growth factor regulation
  • Latter, ossification-specific transcription factors (Runx2 "core binding subunit alpha-1") differentiate them into osteoblasts

  
• Osteoclasts

  • They are members of the monocytes family (tissue macrophages)
  • They erode and absorb previously formed bone

  
• Bone resorption steps


  1. Activated osteoclasts become attached to bone via integrins (membrane proteins) in a membrane extension called the sealing zone

  2. Proton pumps (H+/ATPase) then move from endosomes into the membrane apposed to the isolated area and acidify the area to ~ pH 4.0

  3. The acid dissolves hydroxyapatite and acid proteases secreted by the cell break down collagen, forming a shallow depression in the bone

  
• Cleaning the area after bone resorption

  1. Products of digestion are then endocytosed and move by transcytosis across osteoclasts and released into interstitial fluid

  2. The results of collagen breakdown have pyridinolines that can be measured in urine as an index of the rate of bone resorption

  
• Bone Remodeling

  1. Bone is constantly resorbed and new bone is being formed throughout the life

  2. Bone calcium turns over (changes) rate : 100%/year in infants & 18% /year in adults

  3. Bone remodeling is a local process carried in small areas by population of cells called bone-remodeling units (osteoclasts-osteoblasts)

  4. First: Osteoclasts sorb bone in an area

  5. Next: Osteoblasts lay down new bone in the same area

  
• Modeling drifts


  • The shapes of bones change as bone resorbed in one location and added in another

  
• Cortical bone remodeling


  • Occurs inside the cortical bone (osteoclasts tunnel followed by osteoblasts)

  
• Trabecular bone remodeling

  • Occurs on the surface of the trabeculae

  
• In human skeleton, 5% of bone mass is remodeled by 2 Million bone-remodeling units at any one time

  
• Bone renewal rate


  • Compact bone : 4%/ year
  • Trabecular bone: 20%

  
• Remodeling inducer

  The remodeling is related in part by the stress and strains imposed on the skeleton by gravity