Plasma Calcium regulation 5 Flashcards
How much Calcium is in adult human?
Approx 1Kg
How much calcium found in skeleton and teeth?
How much in intracellularly in soft tissues?
How much in extracellular fluid - how is it split up, can it interact with cells?
99% of Ca2+ is in crystalline form within the skeleton and teeth.
0.9% is found intracellularly within the soft tissues.
<0.1% present in the extracellular fluid (ECF)
About half of ECF Ca2+ is either bound to plasma proteins or complexed with PO4^-3, hence not available for cellular reactions
Other half can readily pass to from plasma into ICF and interact with the cells.
Note - which Ca^2+ is active and subject to regulation and what does this constitute to?
Only free ECF Ca2+ is biologically active and subject to
regulation; it constitutes less than one thousandth of the total calcium in the body
How much Ca^2+ in plasma and intracellularly?
Plasma Ca2+ : approx 2.2 - 2.6mmol/L
Intracellular Ca2+ : approx 100nmol/L
Physiological role of Calcium? 13
- Muscle contraction
- Structural integrity of bones and teeth
- Blood clotting
- Enzyme regulation
- Membrane stability
- DNA/RNA synthesis
- Neurotransmitter release
- Secretion
- Intracellular signaling
- Proliferation
- Fertilization
- Cell motility
- Maintenance of tight junctions
6 Roles of Free ECF Ca^2+?
- To prevent aberrant neuromuscular excitability
- Excitation-contraction coupling
- Stimulus-secretion coupling
- Excitation-secretion coupling
- Maintenance of tight junctions
- Clotting of blood
Role of Free ECF Ca^2+ to prevent aberrant neuromuscular excitability?
A fall in free Ca^2+ causes overexcitability of nerves and muscles and a rise in free Ca^2+ depresses neuromuscular activity
Excitation-contraction coupling is a role of Free ECF Ca^2+?
In cardiac and smooth muscle - resulting from increased calcium ions permeability in response to an action potential
Stimulus-secretion coupling is a role of free ECF Calcium ions?
What is this important for?
Entry of Ca2+ into secretory cells, (resulting from increased permeabilty to Ca2+ in response to appropriate stimulation) triggers the release of secretory products by exocytosis.
This is important for release of Neurotransmitters by nerve cells and for peptide and catecholamine hormone secretion by endocrine cells
Excitation-secretion coupling - role of free ECF Calcium ions?
In Pancreatic beta cells, Ca2+ entry leads to insulin secretion.
Maintenance of tight junctions between cells - role? free ECF Ca^2+
Ca2+ forms some of the intracellular cement that holds particular tight junctions together.
Clotting of blood - free Calcium ions role ECF?
Ca2+ acts as a co-factor in several steps of the cascade that lead to clot formation
Function of skeleton in regards to calcium?
Storage depot for calcium ions and phosphate ions which can be exchanged with the plasma to maintain plasma concentration of these electrolytes
How much of Calcium ions is in the bone?
99%
Bones are continually being turned over - approx every 10 years - why?
- Maximal effectiveness in its mechanical uses
- Helps maintain plasma Ca2+ levels.
3 types of bone cell:
Osteoblasts, osteocytes and osteoclasts
Osteoblasts function?
Secrete extracellular organic matrix within which the Ca3(PO4)2 crystals precipitate.
Osteocytes function?
Retired osteoblasts imprisoned within the bony wall they have deposited around them.
Osteoclasts function?
Reabsorb bone in their vicinity; break down the
organic matrix.
Where do osteoblasts and osteoclasts trace their origins to?
Where are osteoblasts derived from - what type of tissue is this?
What do osteoclasts differentiate from?
What are macrophages?
Bone marrow
Derived from stromal cells which is a type of connective tissue in the bone marrow
Osteoclasts differentiate from macrophages
Tissue bound derivatives of monocytes
In a unique communication system osteoblasts and their immediate precursors produce 2 chemical signals that govern osteoclast development and activity in opposite way - what are they?
RANK ligand and osteoprotegerin
RANK ligand to bone mass?
Osteoprotegerin- OPG to bone mass?
Decrease bone mass
Increase bone mass
SLIDE 10 DIAGRAM of the role of osteoblasts in governing osteoclast development and activity
Do RANK L and OPG increase/decrease osteoclast action and what does this do in terms of osteoblasts?
RANKL increase osteoclast action which outpaces osteoblast action and thus decreases bone mass
OPG blocks action of RANK by binding to it thus decreasing osteoclast action and osteoblast action outpaces osteoclast action which increases bone mass
Mechanical stres favors?
Bone deposition
What does bone mass decrease with?
Age - Bone density peaks at 30, then declines after age 40. By 50-60 years bone resorption often exceeds bone formation
Bone mass decreases in people confined to bed
Mechanical stress factors bone deposition what about in a child?
Bone builders are influenced by IGF1 + GH and they keep ahead of the bone destroyers
Mechanical factors adjust the strength of bone in response to the demands placed on it - what does this mean?
The greater the physical stress the greater the rate of bone deposition. Eg bone of athletes.
What does osteoporosis bones look like?
Porous bones
They have a reduced density of the bones when compared to normal ones
What is osteoporosis?
Reduced deposition of the bones organic matrix
– reduced osteoblast activity and/or increased osteoclast activity.
Who does osteoporosis occur more frequently in?
Perimenopausal and postmenopausal women
What are the skeletons of elderly men and women at their peak of?
Skeletons of elderly women are only about 50-80% as their peak at age 35.
Skeletons of elderly men remain at 80-90% of their peak.
Which 3 hormones regulate plasma concentration of calcium ions (and phosphate ions)?
Calcitonin (Thyroid gland)
Parathyroid hormone (PTH) (Parathyroid gland)
Vitamin D (cholecalciferol)
– (also Growth hormone regulates Ca2+ levels)
Regulation of plasma calcium ions depends on hormonal control of exchange between ECF and? 3
Bone (bone calcium flux; important in short-term)
Kidneys (renal excretion)
Intestine (GI absorption)
Organs involved in regulation of homeostasis are: bone, kidney, & gastrointestinal tract, but Ca2+ participates in the function of? Give examples?
Ca2+ participates in the function of most, if not all, cells.
Examples: myocontraction, nerve transmission, coagulation of blood, activation or inhibition of enzymes, hormone function, exocytosis, cell-cell
interaction, cell duplication, and 2nd messenger function
What do the parathyroid hormone (PTH) glands look like and what are they associated with, where are they embedded and how many on each side?
Small oval glands associated with thyroid
Embedded in thyroid capsule or thyroid
Normally 2 on each side (some have 5-6)
PTH is a major controller for?
Does PTH control calcitonin?
PTH major controller of Ca2+ levels
Calcitonin for fine adjustments
The principle chief cells of the PTH gland secrete PTH in response to?
Low blood calcium levels
PTH increases serum calcium ion levels, what 3 responses does this cause?
Increases bone calcium release
Promotes kidney renal tubule reabsorption
Increases absorption from small intestine (via Vit D activation)
How is PTH essential for life?
Prevents fatal hypocalcemia
Thryoidectomy is the surgical removal of all/part of thyroid gland - does it remove PTH gland - what happens here?
Thyroidectomy: usually removes parathyroid gland - can be fatal - but PTH producing cells cluster outside parathyroid gland along trachea
PTH uses bone as a bank to maintain?
Ca^2+ plasma levels
2 major effects of PTH on bone?
1) Induces a fast Ca2+ efflux into the plasma from the small labile pool of Ca2+ in the bone fluid.
2) Stimulates bone dissolution, promotes a slow
transfer into the plasma of Ca2+ and PO4^-3 from the
stable pool of bone minerals in bone itself.
Entombed osteocytes and surface osteoblasts are interconnected by?
Long cytoplasmic processes that extend from these cells and connect to one another within the caniculli.
What does this interconnecting cell network: the osteocytic-osteoblastic bone membrane do?
Separates the mineralised bone from the plasma in the central canal
Where does bone fluid lie between?
Membrane and mineralised bone
See diagram on slide 18
What happens during fast exchange of Calcium ions between bone and plasma?
In a fast exchange, Calcium is moved from the labile pool in the bone fluid into the plasma by PTH-activated Ca^2+ pumps located in the osteocytic-osteoblastic bone membrane.
What happens during slow exchange of Calcium ions between bone and plasma?
In a slow exchange, Calcium ions are moved from the stable pool in the mineralised bone into the plasma through PTH induced dissolution of the bone by osteoclasts
Source and control of calcitonin?
calcitonin 32 amino acids
From C cells (parafollicular cells) of thyroid gland
High plasma Ca2+ = high calcitonin secretion
Function of calcitonin?
Antagonist to PTH
Lowers plasma calcium ion and phosphate levels
When is calcitonin important and is there any effect of deficiencies?
Important only during hypercalcemia and no effect of deficiencies
What does calcitonin effect of lowering plasma calcium ion levels do?
─ inhibits bone osteoclasts and osteoblasts
─ stimulates Ca2+ secretion via kidneys
─ increases production of inactive Vit D - 24,25DHCC
Feedback of PTH and Calcitonin secretion?
Negative
Decreased plasma calcium ions effect?
Positive on PTH gland - increases PTH thus increasing plasma calcium levels
Negative on thyroid C cells - increases calcitonin and decrease plasma calcium ion levels
Increased plasma calcium ions levels?
Positive effect on thyroid C cells - increases calcitonin which decreases plasma calcium ion levels
Negative on PTH glands - increases PTH which increases Plasma calcium ion levels
Source and control of vitamin D?
Cholesterol derivative when exposed to
sun
Supplemented by diet
Activated by liver, then kidneys
Function of Vitamin D? 3
Essential for GI calcium and phosphate
absorption
Increases renal calcium reabsorption
Regulates activity of osteoblasts and osteoclasts
What form is Vitamin D in when first enters the blood?
Biologically inactive
What dies activation of Vitamin D involve?
Requires 2 sequential biochemical alterations; adding hydroxyl groups: step 1 occurs in the liver and step 2 in the kidney
The kidney enzymes involved in step 2 are stimulated by, in response to what?
PTH in response to a fall in plasma calcium ions
SEE DIAGRAM SLIDE 22 OF VITAMIN D ACTIVATION
Process of vitamin D being made:
7-dehydrocholesterol –UV–Skin–> Cholecalciferol Vitamin D3—liver—> 25 hydroxy cholecalciferol (calcutrol) —-kidney—> 1,25-dihydroxycholecalciferol (Vitamin D)
REVIEW:
SLIDE 23: Interactions between PTH and Vitamin D in controlling plasma calcium
SLIDE 24: Control of plasma phosphate
Primary disorders of Ca^2+ metabolism are related to?
Too much or too little PTH or Vitamin D deficiency
What is PTH hypersecretion: hyperparathyroidism
What is it characterised by?
Hyper secreting tumour in one of the PTH glands – characterised by hypercalcemia and hypophosphatemia.
Possible consequences of PTH Hypersecretion?
Reduced excitability of nerves and muscles – muscle
weakness, neurological disorders, decreased alertness, poor memory and depression. Cardiac disturbances may also occur
What can excessive mobilisation of calcium and phosphate ions from skeletal stores lead to of PTH hypersecretion?
Bone thinning
Possible consequences of excessive mobilisation of calcium and phosphate ions during PTH hypersecretion?
Skeletal deformaties and increased incidence of fractures
Increased incidence of calcium ions containing kidney stores can cause during PTH hypersecretion?
Excessive filtering through kidneys may precipitate
Possible consequences of increased incidence of Ca2+ containing Kidney stones – excessive calcium filtering
through kidneys may precipitate?
Extreme pain as stone passes through the ureters
What can hypercalcemia also account for?
Peptide ulcers, nausea and constipation
What disease is called one of “bones, stones and abdominal groans”?
Hyperparathyroidism - PTH hypersecretion
Total removal of PTH?
Death
PTH Hyposecretion: Hypoparathyroidism due to?
Used to be due to inadvertent removal of parathyroid glands during surgical removal of the thyroid.
Rarely PTH hyposecretion results from an autoimmune attack against the parathyroid gland.
What does PTH Hyposecretion lead to?
Symtoms?
Leads to hypocalcemia and hyperphosphatemia.
Symptoms: increased neuromuscular excitability (reduced Ca2+ level)
Possible consequences of PTH Hyposecretion?
Muscle cramps and twitches from spontaneous activity in motor nerves and tingling and pins and needles sensations result from spontaneous activity in sensory neurons.
Mental changes including irritability and paranoia.
Vitamin D deficiency in children and adults?
Rickets in children
Osteomalacia in adults
What is a Vitamin D deficiency due to?
Impaired intestinal absorption of calcium ions
In the face of reduced calcium ion uptake, PTH maintains plasma calcium ions levels at the expense of bone
Consequence of Vitamin D deficiency to the body?
Bone matrix not properly mineralised, Calcium ion salts not there for deposition
Bone becomes soft and deformed, bowing under the pressure of weight bearing
- Where is calcitonin made?
- What does it do to Ca ion levels?
- What type of adjustments does it make?
- What is it to PTH?
- What does it do to osteoclasts and osteoblasts?
- Effect on Calcium ion secretion?
- Effect with Vitamin D?
- Thyroid gland
- Lowers Ca^2+
- Fine adjustments
- Antagonist to PTH
- Inhibits bone osteoclasts and osteoblasts
- Stimulates Ca2+ secretion via kidneys
- Increases production of inactive Vitamin D
- PTH is made and by which cells?
- What type of job does it have?
- What does it do to Calcium ion levels?
- What is it to calcitonin?
- Does it increase/decrease calcium ion release?
- Effect on kidney renal tubule reabsorption?
- Effect with small intestine in regards to Vitamin D?
- PTH gland by principle (chief) “C cells”
- Major controller
- Increases Ca2+
- Antagonist to calcitonin
- Increases bone Ca2+ release
- Promotes kidney renal tubule reabsorption
- Increases absorption from small intestine (via Vit D activation)
- Vitamin D (cholecalciferol) when is it made?
- Effect on GI and renal Ca^2+ absorption?
- Effect on osteoblasts and osteoclasts?
- Synthesised from cholesterol when exposed to sun dietary intake activated by liver then kidneys
- Increases GI and renal Ca2+ absorption
- Regulates activity of osteoblasts and osteoclasts
