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
Where is the bone degradation product released?
Transcytosed and released into the interstitial fluid
Which collagen breakdown product present in urine is an index of bone resorption activity?
Pyridinoline
How are osteoclasts involved in the acute regulation of calcium homeostasis?
They are NOT involved in the acute regulation, as they function with a slow response
Which cells do vitamin D and PTH stimulate during bone remodeling? What are the effects?
- Osteoblasts on bone surface
- Secrete OAFs (osteoclast activating factors)
Which cells phagocyte debris following osteoclast bone resorption?
Macrophages
How does calcitonin influence osteoclast activity?
Calcitonin directly inhibits osteoclast activity
Which hormones stimulate osteoblasts to produce OAFs?
PTH and calcitriol
How does PTH affect renal function?
- Increases renal reabsorption of calcium from urine
- Inhibits reabsorption of phosphate
Which areas may calcium be retrieved?
- Bone
- Urine
- Gut
How is parathyroid related protein (PTHrP) similar to PTH? How is it different?
- Similar in structure and can bind to the PTH receptor
- NOT produced by many tissues in the fetus and adult
- Produced and acts locally (paracrine)
What is the major function of PTHrP?
- Required for normal development
- Regulator of the proliferation and mineralization of chondrocytes
- Regulator of placental calcium transport
How does PTHrP usually act?
In a paracrine fashion
What are the consequences of overexpression of PTHrP by a tumour cell?
Produces severe hypercalcemia by activating the PTH receptor
How do the two GPCRs for PTH differ in terms of their affinity for PTH and PTHrP?
- PTHR-1 binds PTH and PTHrP with equal affinity
- PTHR-2 binds only PTH
- These receptors have DIFFERENT tissue distributions
Where is PTHR-1 located?
In bone and kidney tissues
What is osteopetrosis? What is the cause?
- Increase in bone density
- Due to defective osteoclasts
- Bones become more brittle (lose their flexibility)
What is osteoporosis? What is the major consequence?
- Excess osteoclast function
- Frequent fractures in areas with trabecular bone (distal forarm, vertebral body, hip)
What is involutional osteoporosis?
Loss of bone density with age
How does bone mass vary through life stages in men?
Loss of bone mass throughout adulthood
How does bone mass vary through life stages in women?
1) Females have less bone mass to begin with
2) Menopause (transient, rapid decrease in bone loss)
3) Post-menopause (secondary decrease in bone density due to changes in estrogen production)
How does estrogen affect osteoclast activity?
Estrogen down-regulates osteoclast activity
What are the two mechanisms of action by which estrogen normally down-regulates osteoclast activity?
1) Inhibition of cytokines that stimulate the development of osteoclasts
2) Stimulation of the cytokine TGF-B that causes apoptosis of osteoclasts
What occurs at menopause that affects osteoclast activity?
Estrogen levels decrease, which causes osteoclast activity to increase
What are the drawbacks of estrogen therapy to prevent osteoporosis?
- Increases myocardial disease and strokes
- Breast cancer (estrogen is a powerful mitogen)
- Endometrial cancer
- There must be a risk-benefit assessment
What are the characteristics of primary hyperparathyroidism?
- Characterized by increased parathyroid cell proliferation
- Increase PTH secretion
Primary hyperparathyroidism is (dependent/independent) of calcium levels.
independent
What are possible causes of hyperparathyroidism?
- Radiation exposure
- Lithium
- Associated with the loss of tumour-suppressor genes
What are signs and symptoms of primary hyperparathyroidism?
“Stones, bones, groans, and psychic moans”
- Renal stones
- Radiologic “osteoporosis” because calcium is mobilized from bones
- Constipation, indigestion (groans)
- Lethargy, fatigue, depression (psychic moans)
Describe the vicious cycle of hypercalcemia.
1) Hypercalcemia leads to anorexia, nausea, and vomiting, as well as renal salt and water loss
2) This leads to ECF volume contraction, which causes decreased calcium excretion, further aggravating the hypercalcemia
What is the treatment for hyperparathyroidism?
- Removal of affected parathyroid glands
- Autotransplantation of parathyroid tissue to the arm muscle, as it is easier to surgically adjust in this location
What is a possible result following the removal of affected parathyroid glands in a hyperparathyroidic patient?
May result in hypoparathyroidism
PTHrP secreting tumours may result in which condition?
Hypercalcemia
Which hormone has a paradoxical effect, and is used to treat osteoporosis?
PTH
How does PTH function as a treatment for osteoporosis?
- PTH stimulates osteoclastic activity, but, paradoxically, PTH can be used to treat osteoporosis
- PTH is active on osteoprogenitor cells that result in the proliferation and differentiation of OSTEOBLASTS
- Also, PTH inhibits apoptosis of the osteoblasts themselves
What are the catabolic effects of continuous exposure of osteoblasts to PTH mediated by?
Increased expression of M-CSF and RANKL, and a concerted decrease in osteoprogerin
What are the four possible causes of hypoparathyroidism?
1) Failure to secrete PTH
2) Altered responsiveness to PTH
3) Vitamin D deficiency
4) Resistance to vitamin D
What is the major clinical symptom of hypoparathyroidism?
Tetany (increased neuromuscular excitability)
What is the treatment for hypoparathyroidism?
Calcium and some form of vitamin D
How does an increase in calcium concentration affect PTH and calcitonin release?
- Decreases PTH release
- Increases calcitonin release
What are the known hormones that reduces hypercalcemia?
Calcitonin is the only known hormone that reduces hypercalcemia
What are C-cells derived from? Where are they contained?
- Derived from neural-crest cells
- Dispersed among follicular cells
What are the phenotypic consequences of an overproduction of calcitonin?
There are no phenotypic consequences
Alternative splicing of the calcitonin gene produces which protein?
Calcitonin gene-related protein (CGRP)
What are the functions of CGRP? Where is it made predominantly?
- Made predominantly in the nervous system
- Acts as a neurotransmitter
- May act as a very potent vasodilator via a GPCR
How does calcitonin affect osteoclast activity?
- Osteoclasts have calcitonin receptors (GPCR)
- Inhibited by the binding of calcitonin (reduces bone resorption)
How does calcitonin affect renal tubules?
Increased calcium excretion
Is calcitonin essential to calcium homeostasis?
No
What is used clinically as an inhibitor of osteoclastic bone resorption? Which conditions does it treat?
- Calcitonin
- Hypercalcemia or osteoporosis
What are the effects of vitamin D deficiency?
- Leads to bone defects
- Rickets in children, which causes bone deformation and the loss of calcium and phophate from the bone
Vitamin D3 can be formed in the skin from which compound? What does it require?
- 7-dehydrocholesterol
- Requires sunlight (UV light)
Where is vitamin D modified?
1) Hydroxylation in the liver (25-hydroxy)
2) Hydroxylation in the kidney (1,25-hydroxy)
How is vitamin D2 synthesized?
- It is not synthesized
- Vitamin D2 is a pharmaceutical product made by irradiating ergosterol
What is vitamin D2 used for?
Food fortification, such as margarine and milk
The formation of vitamin D3 is affected by what?
Age of skin, pigmentation, intensity of the sun, length of exposure
How may toxic levels of vitamin D3 be achieved with sun exposure?
Toxic levels of vitamin D3 may never be achieved with sun exposure
How may skin production of vitamin D3 be limited?
- By the season
- By the time of day
- By the quantity of sunscreen utilized
How is vitamin D transported in circulation?
- Vitamin D-binding protein (85%)
- Albumin (15%)
What does pre-vitamin D3 produce with UV light?
7-dehydrocholesterol
What does pre-vitamin D produce from the rotation of the A-ring?
Vitamin D3 (cholecalciferol)
What is the consequence of continued exposure to UV-light in terms of vitamin D?
Formation of inactive compounds from pre-vitamin D3
Where does the first hydroxylation of cholecalciferol occur? What does it form?
- Liver
- 25-OH-cholecalciferol
Where does the second hydroxylation of cholecalciferol occur? What does it form?
- Kidney
- 1,25-dihydroxycholecalciferol (calcitriol)
What occurs to the enzymatic activity of 1-hydroxylase as calcium concentration increases? What occurs to the enzymatic activity of 24-hydroxylase?
- 1-hydroxylase has a high enzymatic activity, and drops suddenly as concentration increases past a set-point
- 24-hyroxylase has a low enzymatic activity, and increases suddenly as concentration increases past a set-point
What occurs to the enzymatic activity of 1-hydroxylase as phosphate concentration increases? What occurs to the enzymatic activity of 24-hydroxylase?
- 1-hydroxylase decreases as phosphate concentration increases
- 24-hydroxylase increases as phosphate concentration increases past a certain set-point
What does 1-hydroxylation yield?
- 1,25-dihydroxyvitamin D3
- Biologically active
What does 24-hydroxylation yield?
- 24,25-dihydroxyvitamin D3
- Role is unknown
Which derivatives of vitamin D3 does vitamin D binding protein bind to mostly? Which does it also bind to, but to a lesser extent?
- Binds more to 25-OH-cholecalciferol
- Binds to calcitriol to a lesser extent
ALL physiological effects of vitamin D appear to be due to which vitamin D metabolite?
1,25-dihydroxyvitamin D3 (calcitriol)
How does a decrease in plasma calcium affect the kidney enzymes for vitamin D synthesis?
- Increases PTH
- Increases kidney enzymes
How does a decrease in plasma phosphate affect the kidney enzymes for vitamin D synthesis?
Increases kidney enzymes
What kind of receptor is the vitamin D receptor?
Type II intracellular receptor (nuclear)
How does vitamin D affect osteoblast activity?
Increase
How does vitamin D affect osteoclast activity?
Increase
How does vitamin D affect intestinal calcium and phosphate absorption?
Increase
How does vitamin D affect renal vitamin D degradation (catabolism)?
Increase
How does vitamin D affect parathyroid hormone synthesis?
Decrease
Where is the primary location of gastrointestinal absorption of dietary calcium?
- The distal portions of the GI tract
- Illeum
What are the two different pathways for calcium absorption across the intestinal epithelium?
1) Passive pathway (between cells)
2) Active pathway (transcellular)
What drives the passive pathway for calcium absorption across the intestinal epithelium?
Driven by the concentration gradient
What is the active pathway for calcium absorption across the intestinal epithelium modulated by?
Calcitriol
How does calcitriol promote active calcium uptake in the intestine?
By maintaining a calcium gradient
What occurs within intestinal epithelial cells once calcium is uptaken?
1) Binding to myosin/calmodulin complex
2) Move to the bottom of the microvilli
3) Free calcium in cytoplasm is released by exocytosis or pumps
Calcitriol affects the synthesis of which protein within intestinal epithelial cells? What is its function?
- Calbindin
- Binds calcium to maintain the calcium gradient by mopping up all the free calcium at the bottom of the microvilli
Which organs may vitamin D affect?
- Thyroid (calcitonin)
- Gonads (progesterone, testosterone)
- Pituitary (ACTH, cortisol)
How may vitamin D toxicity occur? What does toxicity depend on?
- Overdose either therapeutically or accidentally
- Depends on differences in storage, catabolism and absorption among individuals
What are symptoms of vitamin D toxicity?
- Weakness
- Lethargy
- Nausea
- Hypercalcemia
- Hypercalciuria
What may chronic overuse of vitamin D lead to?
Ectopic calcification of the kidneys, blood vessels, heart, lungs, skin
What is the treatment for vitamin D toxicity?
- Reduced calcium intake
- Reduced vitamin D intake
- Rehydration
- Cortisol
- Time
Why is cortisol used for vitamin D toxicity?
Antagonizes the action of vitamin D on gut absorption of calcium
How may vitamin D deficiency occur?
- Inadequate sunlight
- Malnutrition
- Malabsorption
What are the effects of vitamin D deficiency in children and in adults?
- Rickets (children)
- Osteomalacia (adults)
