Calcium & Phosphate

Connection between calcium & phosphate

They are generally absorbed together

Why do calcium levels need to be so well regulated but not other things like glucose levels

Blood sugar levels can go from 80 to 280 and it won't do any damage

If calcium levels go too high or too low it can be fatal

When would calcium levels be measured

Calcium levels are measured for seizures, low mood, muscle spasms, etc.

Function of Bone

•Structural support
•Protection of internal organs and soft tissues from damage
•Locomotion
•Mineral storage
•Production of blood cells
•Endocrine regulation

What percentage of bone is liquid - why?

1% liquid bone - able to exchange freely with blood

Composition of bone (organic, inorganic, water)

what is the inorganic part of bone made up of

Hydroxyapatite Crystals Ca₁₀(PO₄)₆(OH)₂ embedded in collagen matrix

Purpose for crystals in bone

Crystals make it easier to dissolve - increase solubility of bone

Role of the inorganic part of bone

Provides structural strength
Facilitates bone regeneration

What other ions are present in inorganic bone

Na⁺, K⁺, Mg²⁺, CO₃²⁻, Ba²⁺, and Zn²⁺

Role of other ions present in inorganic bone

Reduce the crystallinity of bone minerals
Alter solubility Facilitating bone adaptation

What makes up the organic portion of bone

Collagenous Proteins - mostly Type I collagen

what other structures are also made of type1 collagen

Ligaments and Tendons

Structure of collagen

Triple helix structure

What other non-collagen structural proteins make up the organic portion of bone

Proteoglycans - Macromolecules with core polypeptide and glycosaminoglycan (e.g. Hyaluronic acid)

Sialoproteins - highly glycosylated and sulphated phosphoprotein

Bone specific proteins - osteocalcin, osteonectin, osteopontin, RANKL

Proteoglycans function

Organisation of Bone Extracellular Matrix, Collagen Fibrillogenesis

Sialoproteins function

Mineralization and Bone Formation

Osteocalcin function

Bone Formation and Osteoclasts Activity

Osteonectin function

Modulate GF Activity, Cell adhesion, Mineralization

Osteopontin function

Regulates Bone Formation, Migration, Adhesion, & Mineralization

RANKL (Receptor Activator of Nuclear Factor κ-B Ligand) function

Regulation of Bone Resorption

RANKL activates RANK

RANK aids in differentiation of osteoclasts

What is found in trace amounts in organic bone

Growth factors & cytokines

Functions of organic portion of bone

Provides structural support
Contributes to mechanical properties of bone
Flexibility
Resistance to tensile forces

3 types of bone cells

Osteoblasts, osteoclasts, osteocytes

Osteoclasts structure

Large multinucleated giant cells

Have ruffled ends for dissolving bone

Osteoclasts function

Bone Resorption
• Degradation of proteins by enzymes
• Acidification

Osteoblasts function

Bone formation - synthesis of matrix proteins (type 1 collagen, osteocalcin, etc.)

Mineralisation

Activation of osteoclasts via RANKL production

How do osteoblasts stimulate osteoclasts

Parathyroid hormone is found on the osteoblast - it stimulates the osteoclast

Osteoblasts they have a Rank Ligand (RANKL). When RANKL binds with RANK it stimulates the osteoclasts short term

What becomes encased to produce osteocytes

Osteoblasts become encased in bone

A = Osteoblast

B = Osteoclast

C = Osteocyte

How does the body maintain a constant level of calcium

When calcium is low, bone is broken down to release calcium.

When calcium is high, bone is produced to release calcium.

Calcium levels need to be monitored in immobile/paralysed patients as bones are being dissolved and not replaced

What will you see on the bone of someone who has a lack of calcium

If a person has a lack of calcium they will have lots of little pits that are acidic as the osteoclasts work best in that pH - they make acid that will dissolve the bone

what do osteoclasts use to dissolve bone

Osteoclasts have lots of CA. They use it on H2O and CO2 to produced H+

Bicarbonate ions are pumped out of osteoclasts in exchange for chloride ions

Hydrogen ions and chloride ions combine to form HCl - dissolves bone

CA = carbonic anhydrase

Bone remodelling diagram

What is released when bones are broken

 Calcium, phosphates & collagen fragments

Wolff’s Law

Bone grows or remodels in response to the forces or stresses placed on it

What type of bone growth occurs in response to stress

Appositional growth - Growth in diameter

Heavy use of bones leads to …

heavy bones

Non use of bones leads to …

Atrophy

How does Wolff’s Law work

Bone Generates an Electric Charge in Response to Applied Mechanical Stress
Action potential Generated
Osteocytes Release Factors that Stimulate Osteoblastic Activity
Bone growth and Increased Density to Withstand Forces Placed on it

(Piezoelectrical property of bone)

How is the Natural Mechanical Stress Applied to Femur Altered after Total Hip Replacement and why does that matter

Metal Implant Carries Some of the Load Reducing Stress on Femur
Phenomenon is known as Stress Shielding
Loss of Bone Mass Through Resorption After Hip Transplant
Occur Around the Implant Resulting in a Loosening of the Prosthetic Implant
Wolff’s Laws Law On Bone Explained

What hormones determine whether and when bone remodelling occurs

PTH and Calcitonin

where is phosphate found

Bone, ATP, cAMP, proteins etc

Function of phosphate

Regulate cell function

How many grams of phosphate in the body

500-800g

Normal level of plasma phosphate

0.9 -1.3mM

What does phosphate circulate as

Orthophosphate (PO4)

When free phosphate is filtered by the kidney what percentage of it is reabsorbed and what percentage is excreted

85% reabsorbed
15% excreted as urinary buffer

Where is phosphate reabsorbed & by what

Absorbed in intestine by Na+ transporter

How many grams of calcium are in the human body

1100g

Normal plasma calcium levels

2.2-2.6mmol/L

Calcium function

Nerve and muscle excitability, Neurotransmission
Excitation-contraction coupling in muscle
Enzyme co-factor, Bone
Second Messenger, Fertilisation, Mitosis

During what stages 2 in life is most calcium required

9-18 (1300mg)

51+ (post menopausal women) (1500)

Free ionised calcium is tightly regulated (±5%). what happens if it goes too low / too high

Too low = Neuronal hyper-excitability
Too high = Neuronal depression

What causes low albumin

malnutrition, liver disease, or nephrotic syndrome

Effect of low albumin on calcium levels

Total calcium levels might appear falsely low, however the levels of ionized calcium remain unchanged

What measurement provides an accurate reading of calcium

Corrected calcium provides a more accurate reflection of calcium status by adjusting for albumin levels (it measures free ionised calcium - not total calcium)

Corrected calcium (mg/dL) = measured total Ca (mg/dL) + 0.8 (4.0 - serum albumin [g/dL])

4.0 = average albumin level

0.8 = correction factor

How is the ionised fraction of calcium affected by pH

Protein binding decreases as pH decreases

Who is more likely to have hypercalcaemia

People with COPD

(inefficient breathing can increase CO2 levels in blood which decreases pH leading to hypercalcaemic effects)

Who is more likely to have hypocalcaemia

People who get panic attacks

Three primary systems involved in the regulation and homeostasis of calcium in the body

bone, kidney, intestine

Three primary hormones involved in the regulation and homeostasis of calcium in the body

parathyroid hormone, calcitonin, vitamin D

Amount of calcium in the ICF & ECF

ICF = 10^-7M
ECF = 10^-3M

Ratio between ICF & ECF = 1: 10,000

Where in the ICF is calcium stored

Mitochondria and ER

Location of parathyroid gland

Under thyroid

How many parathyroid glands are there generally

4

Role of chief glands in parathyroid gland

Responsible for the synthesis, storage, and secretion of parathyroid hormone (PTH).

They have Ca²⁺ sensing receptors

How do chief cells regulate PTH secretion

Normal or Increased ECF [Ca2+] – Inhibition of PTH

Decreased ECF [Ca2+] – Rapid increase in PTH

Effect of long term Ca²⁺ levels being too high or too low

alter gene transcription, synthesis, storage of PTH

Primary function of PTH

Regulate Ca²⁺ in ECF

Where does PTH act

bone, kidney and intestine

How does PTH act

Low Ca²⁺ → increases secretion of PTH

PTH increases plasma [Ca²⁺]

PTH structure

polypeptide hormone consisting of 84 amino acid residues.

When PTH is released it breaks up into fragments. How long can these fragments remain active for

Peptide fragments can be active for hours

PTH acts via what messenger

cAMP second messenger

Do osteoblasts and osteoclasts both have PTH receptors

Osteoblasts do

Osteoclasts don’t

Why can PTH be used to short term treat ___________ but not long term

Treat osteoporosis

Long-lasting effect to increase bone resorption…
- increases osteoclast activity indirectly via cytokines release from osteoblast
- increases the no. of osteoclasts; decreases the no. of osteoblasts

Increase Ca2+ and Phosphate to ECF

Where is calcium filtered in the blood

Glomerulus of kidney

Path of calcium around glomerulus & process of filtration

Calcium enters the proximal tubule

60%–70% of the filtered calcium is reabsorbed in the Proximal Convoluted & Proximal Straight Tubule

20% of the filtered calcium is reabsorbed in the cortical segments of the loop of Henle

Approx. 10% of the filtered calcium is reabsorbed in the distal convoluted tubule (PTH sensitive reabsorption)

Through what does calcium enter the distal convoluted tubule

TRPV5 channels

Once the CA2+ in in the distal convoluted tubule, what does it do

Calcium binds to calbindin D-28k, an intracellular calcium-binding protein (facilitates transport)

Through what 2 pathways can calcium leave the distal convoluted tubule

Sodium/calcium exchanger (NCX1)
Calcium (ATPase PMCA4)

How does PTH stimulate calcium absorption

Via activation of TRPV5, NCX1

PTH increases the calcium pump to the cell

Interlinking of plasma calcium, bone kidney & liver

Effect of calcium on the intestine

Indirect action to stimulate Ca2+ absorption via activation of Vitamin D
Stimulates 1α-hydroxylase and conversion of 25-hydroxycholecalciferol to 1,25-hydroxycholecalciferol

How does the blood calcium receptor have an effect on PTH release