McCumbee- Calcium Homeostasis Flashcards
Normal plasma concentration of calcium?
Between 8.5 and 10.5 mg/dl
___% of calcium is free ionized calcium, the biologically active form
50
What are the 3 principle organs involved in Ca and Phosphate homeostasis?
Small intestine
Skeleton
Kidneys
The principle regulators of calcium and phosphate homeostasis are _____ and _____
PTH
Vitamin D
What four things are associated with negative calcium balance (net calcium loss)?
Immobilization of a limb
Weightlessness in space
Prolonged bed rest
Certain forms of cancer
Positive calcium balance (net calcium gain) is associated with?
Skeletal growth
Type of bone
Makes up 80% total bone mass
Particularly strong because of a densely packed matrix
Shafts and ends of long bones
Surface of other bones
Cortical bones
Where is cortical bone found?
Shafts and ends of long bones
Surface of other bones
Made of interconnecting bone spicules
Contains 80% of bone surface, but 20% of bone mass
Insides of flat bones
Vertebral bodies
Epiphyses and interior of the diaphysis of long bones
Trabecular bones
Where are trabecular bone found (interconnecting bony spicules)
Inner portion of flat bones
Vertebral bodies
Epiphyses and interior of the diaphysis of long bones
Remodeling of bones is essential for?
Maintaining structural integrity of skeleton
Supporting mineral homeostasis
Which type of bone has the highest yearly remodeling rate?
Trabecular bone (20% per year)
[cortical bone remodels at a rate of 4% per year]
This system is the primary mechanism thru which osteoblasts and osteoblast lineage cells regulate osteoclastogenesis and bone remodeling
OPG/RANK-L/RANK system
RANK-L expression is ______ by PTH and Vitamin D
Stimulated
(RANK-L is the surface ligand on osteoblast lineage cells that tell the osteoclast precursors, which have RANK receptors, where to bind)
RANK-L expression is stimulated by _____ and ______
PTH
Vitamin D
(RANK-L is the surface ligand on osteoblast lineage cells that is where the osteoclast precursor cells are able to bind with their RANK receptors)
RANK-L expression is _______ by estradiol.
Inhibited
(RANK-L is the surface ligand on osteoblast lineage cells that tell the osteoclast precursors, which have RANK receptors, where to bind)
RANK-L expression is inhibited by ______ .
Estradiol
(RANK-L is the surface ligand on osteoblast lineage cells that tell the osteoclast precursors, which have RANK receptors, where to bind)
_________ are able to release OPG (osteoprotegerin), which is a soluble protein that binds RANK-L and prevents it from activating RANK
Osteoblasts and osteoblast lineage cells
________ inhibits RANK-L induced differentiation of proteoclasts when necessary by preventing it to activate RANK in osteoclasts and preosteoclasts.
OPG
OPG production is stimulated by ________
Estradiol
It is inhibited by PTH
OPG production is inhibited by ________
PTH
It is stimulated by estradiol
What does M-CSF do?
Macrophage colony stimulating factor
Promotes the early differentiation of monocyte/macrophage lineage cells and works with RANK-L to PROMOTE osteoclastogenesis
M-CSF also bind receptors in osteoclast precursors causing them to proliferate and enhancing their survival
(Resorption)
Where is M-CSF secreted from?
Osteoblast lineage cells
Osteoprotegin ________ the activity of the RANK-Ligand system
Antagonizes
The osteoclast’s ruffled edge, which forms after sealing zone attaches, releases H+ by ?
H+ ATPase
What are the two things that bound osteoclasts secrete to degrade the bone?
H+ to dissolve the hydroxyapatite crystal
Proteases to digest the matrix protein
What are some bone turnover markers (products of osteoclast mediated bone resorption) that are used to evaluate bone turnover clinically?
Fasting urine calcium
Serum/urine CTX (C-terminal telopeptides of Type 1 collagen)
NTX (N-terminal telopeptide of type 1 collagen)
What is the fate of osteoblasts following matrix formation?
Become lining cells
Differentiate into osteocytes
Undergo apoptosis
Principal bone crystal
Hydroxyapatite
How does vitamin D increase Ca absorption?
At genomic level; increases synthesis of calbindin and TRPV6 [calcium transport protein]
Explain the transcellular intestinal absorption of calcium (this is most active when dietary calcium levels are low)
Ca+ enters enterocyte thru TRPV6 channel. Ca is then bound by calbindin (keeps Ca gradient low and protects cell from harm of high Ca). Calcium is then carried to basolateral membrane where it leaves cell to bloodstream thru either calcium ATPase or a Ca-Na antiporter.
Vitamin D3 ________ Npt2b channel synthesis when dietary phosphate levels are low
Increases
Explain phosphate absorption in intestinal cells
There are paracellular and transcellular routes
Transcellular; PO4 enters cell thru Nptb2 channel (this is a Na-Phosphate cotransporter [IC Na levels kept low by Na/K atpase])
_______ is able to make minute to minute homeostatic adjustments in blood calcium and blood phosphate concentrations
PTH
This is done by altering PTH-sensitive transporters in the nephron
PTH affects TRPV5 (calcium channel in kidney) by ?
X3
Direct phosphorylation
Inducing its transcription
Inhibiting its removal from apical surface of distal convoluted tubule
[this all helps PTH make minute to minute adjustments in blood calcium concentration]
About __-% of calcium in the glomerular filtrate is reabsorbed by saturable active transport mechanism in the distal convoluted tubules.
This mechanism is regulated by PTH
9
PTH ________ urinary phosphate excretion by inhibiting phosphate reabsorption and distal conv tubules (effect on proximal is most important)
Increases
In the kidney, PTH induces the synthesis of ________ in the proximal tubules. This enzyme catalyzes the conversion of vitamin D to the most active form.
1a-renal hydroxylase
What are the three main functions of PTH in the kidney
- Regulate Ca reabsorption
- Increase PO4 excretion
- Make 1-alpha-renal-hydroxylase which converts vitamin D to the most active form.
PTH is secreted by _______ cells of the parathyroid
Chief cells
_________ is a mechanism for controlling the amount of intact PTH released by chief cells
Intraglandular degradation
Why do you want to get rid of phosphate (PTH regulated) when you’re resorbing calcium from bone.
Ca and PO4 can create a precipitate so you want to decrease the likelihood of that.
the ______ terminal of intact PTH hormones is important in determining biological activity
N-terminal region
Synthetic ____ terminals with 1-34 AA’s can induce ALL known actions of PTH.
N
____________ is a way that the chief cells regulate the quantity of intact PTH that is released
Intraglandular degradation
In order to regulate the amount of PTH released. Secretory granules with PTH have proteases that do what?
Degrade intact PTH to inactive C-terminal fragments
In a state of hypercalcemia, what happens to the release of inactive C-terminal fragments of PTH
It increases
In a state of hypocalcemia, what happens to the release of inactive C-terminal fragments of PTH?
It decreases
The principal phsyiological regulator of PTH secretion is the concentration of ionic calcium in ______
ECF
(Chief cells of the parathyroid gland are very sensitives to changes in this)
[2-3% change from the normal [Ca] will elicit a significant response]
In acute hypocalcemia, the chief cells of the parathyroid gland respond within minutes by releasing more pre-formed PTH. If hypocalcemia continues for days, what is the response?
Increase in PTH gene transcription and PTH mRNA stability increase
(If there is an even more prolonged period of hypocalcemia, there is an increase in the rate of chief cell proliferation)
The basal rate of PTH secretion, which is about ___% of maximum rate, is unaffected by Ca levels in ECF.
5
What are inhibitors of the parathyroid glands secretion of PTH (x2)
Vitamin D3 (active)
Calcium rise
Active Vitamin D effects PTH secretion by?
Working on the genomic level to suppress PTH gene expression.
What are the actions of type 1 PTH receptor when PTH or PTH-related protein bind to it
GCPR pathway to increase levels of cAMP
Turn on IP3/diacylglycerol pathway which will activate phospholipase C
PTH ______ the expression of RANK-L
Promotes
PTH _______ the expression of OPG
Down regulates
OPG is the soluble molecule that competes with RANK for RANK-L
The effects of PTH on kidney function are responsible for ?
The minute-to-minute homeostatic adjustments of Ca levels in ECF
What type of signs and symptoms are there of PTH-induced hypercalcemia
Non-specific (weakness, fatigue, loss of appetite, tiredness)
GI (V, pancreatitis, abd pn, constipation, Peptic ulcers {more gastrin})
Neuro: confusion, mild depression loss of concentration
Kidney stones —> decreased kidney function
Decreased membrane excitability
Clinical features of hypoparathyroidism are due to hypocalcemia.
What are some of these symptoms.
Neuronal membranes are extra permeable and excitable.
Hypocalcemic tetany of hand and Traousseau’s sign of latent tetany
What type of serum calcium levels are associated with tetany in the hand
Calcium at 6mg/dl
What are the major causes of hypoparathyroidism
Surgery
Autoimmunity
Rare familial disorder characterized by target tissue resistance to PTH
Pseudohypoparathyroidism
_______ is the most common humoral cause of hypercalcemia in malignancy
PTHrP
During fetal development, PTHrP regulates _______ flux thru the placenta from maternal to fetal circulation
Calcium
form of vitamin D has very little biological activity and a long circulatory half-life.
It is the most abdundant form of vitamin D.
It is the predominant circulating form of vitamin D and thus what is measured clinically when assessing a patient’s vitamin D status.
25(OH)D
Most potent vitamin D metabolite
Formation catalyzes by 1-alpha-hydroxylase in kidney
1,25(OH)2D
What 2 things have an inhibitory effect on 1-alpha-hydroxylase
High plasma calcium
High levels of 1,25(OH)2D
What are target tissues of vitamin D3 (x4)
Small intestine
Bone
Parathyroid glands
Kidneys
More than 99% of the vitamin D and vitamin D metabolites in circulation are bound to plasma proteins. The principal carrier is an alpha-globulin called __________
Vitamin D binding protein (DBP)
In proximal tubules, the entire Vitamin D-DBP binding complex is taken up by receptor mediated endocytosis
What does 1,25(OH2)D do in the intestinal epithelium?
Increases calcium absorption from the lumen.
By increasing expression of epithelial calcium channels
(Also increases expression of calbindin-D9k)
particularly dramatic response in the duodenum where vitamin D receptor concentration is the greatest
Actions of vitamin D on bone?
Works synergistically with PTH to promote mobilization of calcium from bone
Indirect stimulatory effects on bone mineralization
What are vitamin D’s affects on the parathyroid gland?
Negative feedback on PTH secretion by inhibiting expression of gene
Also modulates chief cell response to Ca and Vit D by inducing expression of CaSR and Vit D receptor
What are VItamin D’s affect in bone?
Help w/ proper bone mineralization by making sure Ca and PO4 are there
Promote osteoclasotgenesis by inducing RANK-L expression on osteoblasts and by suppressing osteoprotegerin (OPG) synthesis
How does Vitamin D affect the kidney?
It modulates its own formation by inhibitting 1-alpha-hydroxylase activity and stimulating 24-hydroxylase
What are causes of vitamin D deficiency? (X4)
Malabsorption
Nadequate sun exposure
Defect in activation enzymes
Defect in vitamin D receptor
What is a consequence of Vit D deficiency?
Decreased bone mineralization
Rickets/osteomalacia
How does calcitonin work? (Calcitonin is not a major regulator of calcium homeostasis in humans)
Released in response to gastrin or high Ca levels.
Suppresses bone resoprtion by cAMP-dependent mechanism
Osteoclasts have receptors
What is a clinical use for calcitonin?
Treatment of osteoporosis
What do CaSR (calcium sensing receptors) do in chief cells of parathyroid?
Monitor minute to minute changes in calcium. In stages of high calcium, cause activation of phospholipase A2, increase arachadonic acid, increase leukotrienes which leads to the intraglandular degradation of PTH.
In absence of Calcium, these receptors stimulate PTH release
