Section 12: Mineralized tissues Calcium and phosphate

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Section 12 Mineralized tissues

• Calcium and phosphate metabolism

02/24/06
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Biological Roles

• Calcium
• Mineralized tissue (Ca10(PO4)6(OH)2 in
• bone, dentin, cementum enamel)
• Neuromuscular excitability
• Clot formation
• Cell-cell adhesion
• Intracellular second messenger

• Phosphate
• Mineralized tissue
• Phosphorylated metabolites
• (ATP, UDP-glucose, glucose 6-phosphate creatine
  phosphate, etc.)
• DNA, RNA
• Phospholipids
• Free ortho- pyro- phosphates
• Phosphoenzymes

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Distribution and Requirements

• Calcium
• 99 of Ca2 is in mineralized tissue
• The remainder is mostly extracellular.
• Cytosolic free calcium is closely regulated.
• RDA 800 mg
• Phosphate
• 80 of Pi is in mineralized tissue
• The remainder is mostly intracellular
• RDA 800 mg

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Free and Total Calcium and Phosphate

• Calcium, mM Phosphate, mM
• total free total free
• Blood 2.5 1.2 2 1
• Intracellular low 0.0002 50 6
• Interstitial 1.5 1.2 1 1
• Total calcium includes bound calcium.
• Total phosphate includes phospholipids,
  nucleotides, DNA, RNA, etc.

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Calcium Uptake

• CBP is not required for Ca2 transfer across cell
  membrane.
• Calcium and phosphate transport proteins
  facilitate diffusion.
• Globulins and albumins transport Ca2 in blood
  and buffer its concentration.

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Intake, Uptake and Excretion
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Intake, Uptake and Excretion
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Hormones

• Parathyroid hormone (PTH) is an 84 amino acid
  peptide that is secreted by the parathyroid in
  response to low plasma Ca2.
• 1,25-Dihydrocholecalciferol (1,25-DHCC) is
  synthesized and released from the kidney in
  response to PTH.
• Calcitonin (CT) is an 32 amino acid peptide that
  is secreted by the thyroid. CT reduces plasma
  Ca2 by reducing transfer of Ca2 to the blood
  and inhibiting bone resorption, but it does not
  seem to have a role in normal regulation.

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Regulation of Plasma Calcium

• In bone and in the intestine, calcium and
  phosphate increase or decrease together.
• In the kidney, one increases when the other
  decreases.
• Low Pi increases 1,25-DHCC production
  independently.

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Vitamin D

• Vitamin D is the precursor for synthesis of the
  hormone 1,25-DHCC.
• Hypovitaminosis, due to dietary deficiency, fat
  malabsorption or inadequate exposure to light,
  leads to rickets and to osteomalacia.
• Hypervitaminosis increases calcium uptake and
  resorption. This leads to hypercalcemia,
  hyperphosphatemia, cardiac arrhythmias, and
  ectopic calcification (urinary tract, kidneys,
  arteries).

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1,25-DHCC Synthesis and Action

• Synthetic steps in liver, skin, and kidney.
• Effect on bone
• Rapid mobilization of Ca2
• Increased osteoclast activity
• Effect on intestinal mucosa
• 1,25-DHCC binds a nuclear receptor protein,
  increasing transcription.
• More Ca2 and Pi transport and binding proteins
  are synthesized.

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Bone Structure

• Osteon surrounds blood vessel.
• Lamellae connect osteocytes longitudinally.
• Canaliculi connect osteocytes laterally.

Fig. 19-20 Sherwood
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Osteon schematic detail
Fig. 19-21a , Sherwood

• Bone fluid calcium in the canaliculi is rapidly
  mobilized and transferred to blood by calcium
  pumps in the membrane.
• Mineralized calcium is mobilized more slowly by
  osteoclast activity (not shown here).

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Bone Remodeling

• Osteoblasts form, and osteoclasts resorb bone as
  part of a continuous remodeling process.
• The gene expression control mechanisms are
  beginning to be understood (see Science
  289150115041508 (2000)).
• Osteoblasts
• It appears that osteoblasts are mainly regulated
  by inhibition genes code for the transcription
  factor Cbfa and the secreted protein osteocalcin,
  both of which inhibit activity in mature
  osteoblasts.
• Leptin, which binds receptors on the hypothalamus
  to regulate appetite, also appears to cause the
  hypothalamus to signal osteoblasts to inhibit
  activity.
• Osteoclasts
• PTH stimulates osteoclast production and
  activity.
• Sex steroids regulate osteoclast differentiation,
  which modulates bone resorption.

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PTH modulates osteoblast and ostoclast
activity.But, osteoclasts have no PTH receptor.
PTH
2004 Science 3051420

• PHT decreases OPG production, allowing the
  protein rank-L, also made by osteoblasts, to bind
  the rank-L receptors. This stimulates
  osteoclast production and maturation.

• Osteoblasts produce the protein OPG
  (osteoprotegerin) which binds osteoclast rank-L
  receptors and down regulates osteoclast
  production.

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Osteoclast Mechanism

• Osteoclasts are attached to bone by structures
  called podosomes.
• ATP-driven proton pumps in the osteoclast
  membrane lower the pH in the space between the
  osteoclast and the bone.
• The low pH dissolves hydroxyapetite and degrades
  protein.

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Osteoporosis

• Osteoporosis is a bone remodeling disease that is
  common among post-menopausal women.
• The symptoms are reduced bone volume, density and
  strength.
• These symptoms are due to progressive loss of
  bone calcium and protein, because of reduced
  osteoblast activity and/or increased osteoclast
  activity.
• Increased calcium consumption usually does not
  reverse the symptoms.
• Hormone replacement therapy appears to reduce the
  risk of osteoporosis. Estrogen stimulates
  osteoblasts.
• Increased dietary calcium and exercise during
  earlier years appear to reduce the risk in later
  life.

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Osteoporosis Drug Treatments

• Bisphosphonates.
• Fosamax (alendronate), reduces osteoclast
  activity.
• Side effects with oral administration are mild
  intestinal distress.
• In contrast, intravenous administration of the
  bisphosphonates aredia and zometa for bone cancer
  therapy can be very dangerous. Tooth extraction
  can lead to severe osteonecrosis.

• Forteo (teriparatide). a recombinate human
  parathyroid hormone fragment, 1-34 aa).
• Increases osteoblast activity
• Injected.

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• Next topic
• Ionic solids hydroxyapatite