Part 4: Calcium Balance

Why is calcium critical for normal physiology

• six reasons

• Intracellular signaling

• Hormone secretion

  • Recall insulin lecture and how calcium entry increases insulin

• Blood clotting

• Neural excitability

• Muscle contraction

• Building & maintaining bone

Three locations of calcium

Two places where it is found in the body + percentages

What is special about calcium and its movement?

• extracellular matrix

• extracellular fluid

• intracellular Ca2+

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• Bone: 99%

• Cell: 0.9%

• Extracellular fluid: 0.1%

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Movement

• Cells and bones and output and input with ECF

• Dietary intake to small intestine where it gets absorbed and into the ECF and into bone/cells

• Out calcium through kidney and out in the urine

What is a unique characteristics of bone

• that most people get wrong? Why do we really need this characteristics of bone for everyday life?

• Where is the calcium stored in the bone

• not static, constantly being formed and reabsorbed

  • Purpose: to break away old bone to replace with new bone

  • Especially for repair or micro fracture repair

• Calcium is stored in crystals called hydroxyapatite (calcium + phosphate)

  • Small portion released ionized and readily exchangeable with the ECF

Three cells that make up bone

• and their function

How is bone made

• Percentage turnover for infants vs adults per year

1. Osteoblasts: (Hint: B for build) Bone forming cells - laying down matrix

2. Osteoclasts: (hint: C for cut) Break down bone

• Multinucleated - fusion of multiple cells together and therefore really big

1. Osteocytes: (hint: Sites of maintaining) Maintain bone. (These are previously osteoblasts that are completely surrounded by bone matrix → Therefore just maintain bone in its immediate vicinity

• Tract cell

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• Making bone = creating calcium phosphate complexes)

(calcium crystallization)

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Percentage turnover per year

• infants: 100%

• Adults: 18%

How do osteoclasts break down bone

• a.k.a bone resorption

• Process

  • Include the important equation involved

• Secretes HCL and proteases

• proteases that function well at lower pH and break down the case bone

• Breaking down forms a calcium pool which enters the bloodstream

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• Important equation

  • Carbonic anhydrase enzyme uses carbon dioxide and water to form free protons and bicarbonate

  • Bicarbonate goes to the blood capillary

• Blood capillary brings in Cl, and proton and Cl form HCl

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• HCl dissolves the bone first, and then the proteases breaks it down

How does osteoblasts and osteoclasts communication with each other?

• give a timeline of how it promotes osteoclast formation

• How can it be inhibited?

Initially the osteoblasts are restoring bone

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Osteoclast precursors have receptors

• RANK: receptor activator of nuclear factor kappa B

Osteoblasts have ligands that can bind to the receptors

• RANKL: RANK ligands

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When the osteoblasts receptors and osteoclasts bind together, the ligand activates the osteoclasts receptors to bind together by differentiation and fusion to form the large osteoclast

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Osteoclasts resorbes bone

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Inhibiting

• OPG (osteoprotegerin) will be secreted by osteoblasts to block RANKL/RANK interactions and no resorbing occurs by binding to the ligand

What is osteoporosis

• a condition where there is more bone resorption

What is Denosumab drug?

• helps prevent bone loss

• A monoclonal antibody

• Binds to RANKL to minic OPG and the ligand cannot bind to the osteoclasts

What three hormones control plasma CA2+ levels

• jus list them

What are the three target site

• Hint: remember how calcium flows around in the body and where it goes

• PTH: parathyroid hormone

• Calcitriol

• Calcitonin

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Sites

• Bones

• Kidneys

• Digestive tract

Parathyroid hormone/PTH

• What gland involved

  • Location

  • Process within their cells

• Function

  • What targets sites and what does PTH tell them to do?

• Stimulus

• release from the parathyroid glands

  • Four of them, very tiny, found on the back of the neck, stuck on the the thyroid gland

  • Process in cells

    • GQ protein, as long as there is calcium that acts as ligand, results in kinase phosphorylation that inhibit PTH secretion

    • Kinase phosphorylation also increase vit D3 receptor which prevents the synthesis of the PTH hormone as well

• Function: to increase plasma CA2+ concentration

  • For bone: in osteoblasts increasing cAMP, to increase the release RANKL and decrease OPG (that inhibiting it)

  • For kidneys: reabsorb the Ca2+ found inside the urine back into the blood

  • Calcitriol synthesis

• Stimulus low plasma CA2+

  • Very sensitive: very small range (around 1.2 concentration)

Calcitriol

• another common name for it

• Which organs help in the development of the hormone

• Main function

• Targets which organs and what does it do to each?

• How is calcitriol formed?

  • Process

• The process of calcitriol signalling to target organs

• also known as 1,25-dihydroxycholecalciferol

• Organs

  • Skin

  • Liver

  • Kidney

• Function to increase serum (in the blood) calcium

• Target organs

  • Main affect: Intestines: increase Ca2+ intake (affects this the most)

  • bone: some mobilization (little effect)

  • kidney: reabsorption of the Ca2+ back into the blood (little effect)

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Formation of calcitriol

• In skin have cholesterol precursors for vit D3, the cholesterol gets concerted into vit D3 due to the presence of UV light

• The vit D3 further changed into 25-hydroxycholecalciferol in the liver

• PTH in the kidney activates the cholesterol into calcitriol or vit d3 hormone

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Signalling process

• Calcitriol diffuses through the membrane to binds to the vit D nuelcear receptor

• Forms a heterodimer with another receptor, the retinoic acid receptor

• Heterodimer goes into the nucleus to find the vit D response element

• Stimulate new genes being formed to form more CA channels and binding proterins and transporters in the kidneys and intestines to help absorb or reabsorb calcium into the bloodstream

Three things that can be done to correct a calcium deficit

• what is the main goal

• What do you want the target organs to do

  • What hormones are involved and how are they involved

• main goal: increase Ca2+ concentration in the blood

• Bone: increase resorption

  • Increase PTH

• Kidney: retain Ca2+ and prevent loss

  • Increase PTH which also increases calcitriol

• Intestine: increase CA2+ absorption

  • calcitriol by the help of the increase of PTH

How is blood phosphate controlled?

• recall what is phosphate in relation to calcium

• Why is it important to controll phosphate during the controlling of calcium

• What are the effects of the two hormones on phosphate control in certain target organs (2 target hormones for each)

  • Why are the effects slightly different for each hormone (when is the hormone activated in terms of time)

• Blood hydroxyapatite crystals have both calcium and phosphate

• When calcium breaks down, phosphate also gets broken down

• Hormones

  • PTH: immediate need of breaking of bone and therefore a lot lot LOT of phosphate

    • increase phosphate release in the bone

    • Decrease phosphate reabsorption in the kidney (don’t need a lot being reabsorbed because they would results in too much phosphate in the blood)

  • Calcitriol: hormone is there for day to day life; therefore constantly need calcium

    • Increase phosphate absorption by intestine

    • Increase reabsorption by kidney

Summary of key points of the hormones

1. PTH mobilizes calcium from bone: osteoclasts via RANKL and OPG mechanism (indirectly through

Osteoblasts)

2. PTH enhances renal reabsorption of Ca2+ (and kicks out phosphate!)

3. Calcitriol - PTH enhances the production of Calcitriol

4. Both work at Bone/Kidney/Intestines to increase absorption!

Calcitonin

• Where is it secreted from

  • What unique characteristics does it have in relation for secreting CA2+

• What type of hormone is it

• What triggers its release

• Main function of calcitonin

  • When in parts of life is this most important?

• How does it affect the target organs

• secreted from C cells of the thyroid gland

  • C cells have Ca2+-sensing receptors

• A peptide hormone

• Release triggered by high plasma Ca2+ concentration

• Function: decreases calcium levels to protect the skeleton from Ca2+ loss

  • Important in pregnancy and lactation

• Target organs

  • reduces activity of oseoclasts in bone

  • Stimulate osteoblasts in depositing calcium

  • Inhibit the reabsorption of Ca2+ by kidneys

What happens in calcium homeostasis is not maintained?

• Hypercalcemia (TOO MUCH):

  • GROANS (constipation)

  • MOANS (psychic moans = fatigue, lethargy, depression)

  • BONES (bone pain)

  • STONES (kidney stones)

  • Psychiatric OVERTONES (including depression and confusion) ++Weakness

• Hypocalcemia (TOO LITTLE)

  • C= Convulsions

  • A = Arrhythmias

  • T = Tetany

  • S = Spasms, Seizures, & Stridor

  • > People can die from this

Summary slide for calcium balance

• Cal+ homeostasis is affected by:

  • Dietary intake

  • Urinary output

  • Distribution in bone, cells, and ECF

• Decreased Ca+ stimulates PTH

  • Promotes Cal resorption from bone, enhances renal Cal reabsorption, and increases Ca?+ through its effect on calcitriol