8) Calcium Metabolism Flashcards
Which mechanisms are elicited when there is low blood calcium?
- Parathyroid hormone
- Vitamin D
Which mechanisms are elicited when there is high blood calcium?
Calcitonin
What is the physiological role of calcitonin?
- There is no effect in terms of calcium regulation when calcitonin is removed from the body
- The physiological role of calcitonin in humans is uncertain
What are historical remedies that were used for rickets during the 17th century? What was the active ingredient?
- Fish liver oil
- Sun exposure
- UV-irradiation of certain foods
- Vitamin D
Where is total body calcium largely located?
Within the skeleton
Within the plasma, there is an equilibrium between which two forms of calcium?
- Ionized calcium and bound calcium
- Depending on the calcium used and ingested
What is the quantity of ionized calcium controlled by? Why is it unique?
- It is the ONLY part of calcium metabolism that is regulated
- Regulated by vitamin D and PTH
What are the functions of calcium?
- Required for blood clotting
- Regulation of enzyme activity
- Membrane excitability
- Second messenger of hormone signals
- Muscle contraction
What are the effects of hypocalcemia on the action of neurotransmitters?
- Decreases exocytosis of neurotransmitters
- Results in epilepsy and tetany (spastic paralysis)
How does calcium function as a second messenger of hormone signals?
It is released from the endoplasmic reticulum by the PLC pathway
How is muscle contraction triggered?
By the release of calcium from the sarcoplasmic reticulum
How do the extracellular and intracellular calcium levels compare?
- They are tightly regulated
- Extracellular levels are MUCH HIGHER than intracellular levels
What are the three types of calcium present within normal human plasma? What percentages do they make up?
1) Bound to albumin (50%)
2) Complexed to citrate (8%)
3) Non-complexed (free) ionized calcium (42%)
Which component of calcium within plasma is the most important? Why?
The non-complexed calcium is readily available, and is the most important
What regulates protein-bound and complexed calcium?
- They are NOT regulated, unlike ionized calcium
- They are metabolically inert
Calcium homeostasis maintains constant levels of calcium in the extracellular fluid, while providing enough calcium to which compartments? What does it compensate for?
- Cells, bone, and renal excretion
- Compensates on a constant basis for changes in dietary absorption, bone metabolism, and renal function
What medical condition occurs as a result of overbreathing (hyperventilation)?
Tetany
How is calcium linked to the onset of tetany caused by hyperventilation?
1) Hyperventilation reduces the partial pressure of CO2
2) Less bicarbonate is produced, and H+ levels decrease (alkalosis)
3) H+ is released from serum proteins
4) Negatively charged serum proteins bind to calcium
5) Reduction in free serum calcium causes tetany
How does pH change as a result of hyperventilation?
- Alkalosis
- H+ levels fall
What is tetany?
Extensive spasms of skeletal muscle
What may occur in blood transfusions in which citrate is the anti-coagulant?
May cause tetany
The concentration differential of calcium drives many biological processes. How is the concentration of calcium different between the intracellular, interstitial, and serum?
- Intracellular: 0.1-1 uM
- Interstitial: 1.5 mM
- Serum: 2.5 mM
- 1000-fold difference between the inside and outside of the cell
Which organelles contain a higher concentration of calcium than the rest of the cytoplasm?
- Endoplasmic reticulum
- Mitochondria
What maintains the calcium gradient?
ATP-dependent calcium pumps
How many parathyroid glands are there? Where are they located?
- Adjacent to the thyroid
- 4 glands
- 15% of people have a 5th parathyroid gland
Which types of cells produce PTH? In response to what?
- Chief cells and oxyphil cells
- In response to low levels of ionized calcium in the extracellular fluid
Where are C-cells located in the thyroid gland?
They are located throughout the thyroid gland, and do not have a discrete location
Which type of cell produces calcitonin? In response to what?
- C-cells (also called parafollicular cells)
- In response to high levels of ionized calcium in the extracellular fluid
What mediates the response (secretion or inhibition) of PTH?
- A receptor is located on the chief cells of the parathyroid gland to detect ECF calcium
- The receptor is coupled with a GPCR
- High calcium inhibits PTH secretion
- Low calcium stimulates the release of PTH
What is the half-life of parathyroid hormone?
Very short (2-4 minutes)
How many fragments are parathyroid hormones cleaved into for inactivation?
Two fragments (amino terminus and carboxyl terminus)
What is the issue with immunoassays for PTH?
- The clipping of the cleavage site of PTH renders it bioinactive, which means that it may no longer bind to the PTH receptor
- PTH fragments are not indicative of PTH status in an individual
How are immunoassays designed to measure intact PTH?
- Immunoassays utilize two antibodies
- When both antibodies are present and bind to PTH, it indicates one INTACT molecule of PTH
How does high blood calcium affect the GPCR located on parathyroid cells?
- Decreased cAMP
- Increased IP3
How does low blood calcium affect the GPCR located on parathyroid cells?
- Increased cAMP
- Decreased IP3
What are the two signal transduction systems of the parathyroid gland? What are their respective functions?
1) IP3, which reduces PTH release
2) cAMP, which increases PTH release
How do serum levels of PTH vary as calcium increases?
Serum levels of PTH decrease (inverse relationship)
How do serum levels of PTH vary as calcium decreases due to a calcium chelator (e.g. EDTA)?
Serum levels of PTH increase (inverse relationship)
What are the three target organs of PTH?
- Bone
- Kidney
- Gut
How does PTH affect bone? (2)
- Increases the resorption of bone by stimulating osteoclasts
- Promotes the release of calcium and phosphate into circulation
Which minerals are contained in large quantities within bone?
- Calcium
- Phosphorus
- Magnesium
What are the four types of cells contained within bone?
- Osteoprogenitor cells
- Osteoblasts: build bone
- Osteocytes: former osteoblasts
- Osteoclasts: break down bone
The serum level of which protein is an indicator of bone growth?
Osteocalcin
What are the functions of the bone protein osteonectin? (2)
- Binds collagen and hydroxyapetite
- May serve as a nucleator for calcium deposition in the bone
What are osteoblasts derived from? Where are these progenitor cells located?
- Mesenchymal stem cells
- Fibroblast-like cells located in the bone marrow
Describe the steps of osteoblast differentiation.
1) Mesenchymal stem cells become osteoprogenitor cells
2) Osteoprogenitor cells become osteoblasts
Where are osteoprogenitor cells located?
- Attached to bone surface
- Proliferating
What do osteoblasts secrete? What occurs afterwards?
- Collagen and other proteins to form a matrix
- Mineralization (deposition of hydroxyapatite)
When does primary mineralization occur? When does secondary mineralization occur?
- Primary: 60-70% in 6 to 12 hours
- Secondary: 1 to 2 months
What occurs to osteoblasts following mineralization?
- Entombed osteoblasts differentiate into osteocytes
- Formation of a network of metabolically active cells
Where are the two pools of calcium located within the bone? How do they compare in terms of the speed of their exchange to plasma?
- Calcium present in the bone fluid (fast exchange to plasma)
- Calcium present in the mineralized bone (slow exchange to plasma)
Where are osteoblasts located? Where are osteocytes located?
- Osteoblasts: surface of the central canal or outer surface
- Osteocytes: within the canaliculi
Differentiate compact and trabecular bone in terms of their relation to aging.
- Compact: adult long bones
- Trabecular: epiphysis, fractures, juvenile bone, bone disorders
How does calcium turnover differ between infants and adults?
- Infants: 100% per year
- Adults: 18% per year
What mechanism carries out bone remodeling?
- Osteoclasts dissolve bone
- Osteoblasts lay down new bone
What are factors regulating the balance required for bone remodeling? (2)
1) Mechanical factors
2) Hormonal factors induced by PTH
Bones are a storehouse for _____________ that may act in a paracrine fashion on neighbouring osteoblasts and osteoclasts.
growth factors (e.g. IGF-II produced by osteoblasts)
What are osteoclasts derived from? Where are these progenitor cells located? What do these cells also give rise to?
- Derived from monocytes
- Monocytes are contained within the bone marrow, and also give rise to macrophages
How do osteoclasts attach to bone? What do they form?
- Integrins
- Form a tight seal
How do osteoclasts degrade bone?
1) Proton pumps move from endosomes to the cell membrane, where they pump out H+
2) The acidic pH dissolves hydroxyapatite
3) Acid proteases break down collagen