B6: Cell Bio Exam 2 (7-14) FINAL (copy)

Why talk it out when your adrenal medulla can just flood you with adrenaline instead?

hydroxyapatite

what is the main crystalline salt of bone?

bone, kidney, GI

3 tissues responsible for controlling calcium and phosphate levels

Calcitonin, PTH, activated vitamin D

3 hormones responsible for controlling calcium and phosphate levels

bone

acts as a reservoir for 99% of body calcium

calcium and phosphorus

hydroxyapatite contains:

crystal precipitate

in a physiologic fluid, calcium and phosphate form a ________ _________ – we don't want that, so there are mechanisms of exchange

down

in a normal setting, to not have precipitates in the bloodstream, as calcium goes up, phosphate needs to go _____

PTH

What hormone:

acts to increase plasma Ca²⁺, so there needs to be other  mechanisms to ↓ plasma phosphate to not have precipitates in blood stream 

increases the number of sodium fast channels, hence easier depolarization

how does low calcium increase excitability of cells?

8.5-10.5

normal calcium range:

hypocalcemia

What disorder:

-<8.5mg/dl

-extracellular Ca²⁺ →­ electrical excitability of excitable cells (i.e., sensory and motor nerves and muscle)

-Increases activity of Na fast channels, hence easier depolarization

-Tingling, numbness, muscle twitch/spasms and tetany

hypercalcemia

What disorder:

->10.5mg/dl

-extracellular Ca²⁺ → excitability of excitable cells

-Constipation, kidney stones, bone pain/loss, polyuria/polydipsia, lethargy, coma

-stones, bones, groans, psychiatric overtones

pregnant women

in ______ ______, a negative calcium balance comes from intestinal calcium absorption being less than calcium excretion, with the deficit coming from the maternal bones

growing children

in _______ ____, a positive calcium balance comes from intestinal calcium absorption exceeding urinary excretion, with the excess is deposited in the growing bones

1,25-dihydroxycholecalcirerol

active form of vitamin D

ionized

the most abundant form of calcium:

-hint: rest is bound to albumin (40%) or complexed with anions (10%)

ionined

only ______ calcium is biologically active

albumin

only calcium bound to _______ (protein bound) cannot be filtered

pH & albumin

factors modifying ionized calcium

albumin

increased H+ binds to ______, raising amount of ionized calcium

-low protein bound calcium

-n/c free ionized calcium

-low total calcium

how does hypoalbuminemia (cirrhosis, critical illness) impact calcium levels?

-high protein bound calcium

-n/c free ionized

-high total calcium

how does hyperalbuminemia (hypovolemia, high protein intake) impact calcium levels?

-inc protein bound

-dec free

-normal total

how does alkalosis alter plasma calcium levels?

-dec protein bound

-inc free

-normal total

how does acidosis alter plasma calcium levels?

-inc protein bound calcium

-normal free ionized calcium

-inc total calcium

how does pregnancy alter plasma calcium levels?

phosphate

What ion:

-major intracellular anion/acid-base buffer

-component of all glycolytic enzymes, ATP/DNA/RNA

-uptake from gut is linear with diet levels

-primary regulation via urinary excretion

hyperphosphatemia

What disorder:

-increased phosphate leads to increased binding of free calcium, therefore there is decreased free calcium

refeeding syndrome

what disorder:

-Insulin promotes phosphorus uptake into peripheral cells

FGF23

aka osteokine

-peptide produced by osteocytes

-negative regulator of serum phosphate via ability to inhibit reabsorption in the kidney, promotes excretion

2.5-4.5

normal serum phosphate level

Ricketts (children) & osteomalacia (adults)

hypophosphatemic disorders associated with excess production of FGF23

FG23 mutation

AD hypophosphatemic rickets is due to:

PHEX mutation

X linked hypophosphatemic rickets is due to excess FGF23 secondary to:

FGF23

sometimes ectopically produced by slow-growing occult mesenchymal tumors, causing a hypophosphatemic paraneoplastic syndrome

bone

-in a constant state of resorption/reformation

-metabolically active tissue, has a good blood supply, etc.

-Hydroxyapatites are most abundant mineral crystals; contain calcium/phosphorous in a molar ratio of about 1.7 to 1 (2.2 to 1 weight ratio), with all the phosphorous as phosphate (PO₄^-)

-osteoblasts form new bone, Osteoclasts resorb (Breakdown)

hyperphosphatemia & 1,25 dihydroxyvitamin D

production of FGF23 is increased by:

FGF23

-inhibits 1,25-dihydroxyvitamin D, resulting in decreased phosphate absorption intestinally and renally

calcium sensing receptor in the plasma membrane

how do chief cells monitor calcium levels?

chronic hypercalcemia

What disorder:

-decreases transcription of prepro PTH (as well as post translational processing)

C terminal fragment

PTH derived fragment that is most represented in serum, has a longer half life

within seconds!

how fast does PTH respond to calcium levels?

Magnesium

_______ has parallel, but less important, effects on PTH secretion than calcium

directly

PTH works (directly/indirectly) on bone and kidney

indirectly

PTH works (directly/indirectly) on intestine

kidney

effects of PTH on the ______:

-increase 1-OHase, making more active vitamin D

-increase calcium reabsorption in the distal tubule

-decrease PO4 reabsorption in the proximal tubule

intestines

effects of PTH on the ______:

-indirect

-the increased vitamin D from the kidneys increases calcium and phosphate uptake

bone

effects of PTH on the ______:

-increase reabsorption of mineralized bone, with increases serum calcium

-Phosphate will increase initially

increase serum Ca, decrease serum P

overall action of PTH

Bind to osteoblasts, which respond by activating osteoclasts to resorb bone

how does PTH increase bone resorption?

hydroxyproline (collagen fragments)

increased resorption of organic bone matrix is reflected by excretion of:

those in the kidney!

what effect of PTH happens the quickest?

increased urinary cAMP, decreased serum phosphate, increased serum calcium

PTH inhibits renal phosphate reabsorption on the proximal tubule resulting in:

1,25 dihyddroxycholecalciferol

PTH increases intestinal Calcium absorption indirectly by stimulating ________________ in the kidney

NO!

are there PTH receptors in the intestine?

1. PTH (and Vit D) binds to osteoblasts

2. Osteoblasts release M-CSF and RANK ligand to promote osteoclastogenesis and osteoclast Activity (Bone Resorption)

3. Pre-osteoclasts and active osteoclasts express the RANK receptor

4. Secrete HCl and hydrolytic enzymes

5. As Osteoclasts go through Apoptotic cell death, newly exposed bone matrix releases growth factors and chemokines attracting preosteoblasts

6. Newly formed osteoblasts secrete collagen, proteoglycans and growth factors to replace osteoid matrix

7. Mineralization occurs over weeks once Ca++ becomes available (VitD effect)

how does PTH increase bone resorption?

formation

hormones promoting bone ________:

-androgens, estrogens

-thyroid hormone

-GH, IGF

-calcitonin

-vitamin D

resorption

hormones favoring bone ________:

-PTH

-cortisol

-HIGH thyroid hormone

-inflammatory cytokines

androgens, estrogens, calcitonin

hormones inhibiting bone resorption

increases calcium release

bone resorption's effect on calcium levels

proximal tubule

Actions of PTH on the ________ _________:

-PTH decreases renal phosphate reabsorption in the proximal tubule (i.e., inc phosphate excretion)

-cAMP/PKA activation Phosphorylates NERF proteins which stabilize the Sodium-Phosphate co-transporter (PT) which renders it inactive.

-Phosphate transporters taken out of lumen and degraded via lysosomes

-cAMP generated as a result of the action of PTH on the proximal tubule is excreted in the urine (inc urinary cAMP indicates PTH action)

-PKA activates 1-α-Ohase and CREB which transcribes 1-α-Ohase (converts 25, VitD to 1,25 VitD)

early distal tubule

Actions of PTH on the ___ _____ _____:

-PTH ­inc Ca2+ reabsorption

-Activates/inserts Ca++ transporters on lumen side

-Activates Ca++ ATPase transporters on interstitial side

NERF

cAMP activation on _____ proteins in the proximal tubule results in decreased reabsorption of phosphate in response to PTH

PTH action

urinary cAMP indicates:

1 alpha hydroxylase

enzyme that converts 25, Vitamin D to its active form

-upregulated by PKA in the distal tubule in response to PTH, increasing calcium reabsorption

enhances mineralization

long term effects of vitamin D on bone

increases bone resorption

short term effects of vitamin D on bone

-nucleus of osteoblasts (binding activates osteoclasts)

-GI tract

where are vitamin D receptors located

increase plasma calcium and PO4- so it can be used to promote bone mineralizaiton

what is the goal of Vit D?

vitamin D

a group of related secosteroids either derived from the diet or from metabolism of cholesterol

Ergocalciferol (Vitamin D2)

precursor of vitamin photochemically synthesized in plants

Cholecalciferol (Vitamin D3)

form of vitamin D synthesized in skin in response to sunlight

25-OH vitamin D

when we measure vitamin D levels, this is what we measure

-made in the liver by 25-hydroxylase

1,25-(OH)2 vitamin D

the most biologically active form of vitamin D synthesized by 1-alpha hydroxylase in the kidney

7-dehydrocholesterol

precursor to Vitamain D3 (cholecalciferol)

-converted to D3 by UV light

Vitamin D Binding Protein (DBP)3

Vit D₃ Binds to ______ __ _____ ______, and transport to the liver.

conversion of calcidiol to calcitriol in the proximal tubules by 1-alpha hydroxylase

primary regulatory step of vitamin D formation

1st: 25-hydroxycholecalciferol on the liver

2nd: 1,25 hydroxycholcalciferol

negative feedback of vitamin D production

25-hydroxycholecalciferol stays relatively constant, regardless of D3 intake; represents negative feedback

why do we measure 25, Vit D to assess vitamin D status?

-decreased calcium

-increased PTH

-decreased phosphate

1 alpha hydroxylase activity is increased by:

-increased 1,25 Vit D activates 24-OHase, which converts vit D to an inactive form (1,24,25 vitamin D) that can be excreted in bile

negative feedback regulator of 1,25 Vit D

FGF-23

_____________ represses 1a-hydroxylase activity to reduce phosphate absorption

freely enters cells and binds to DNA receptor

signaling of Vit D (a steroid hormone!)

-stimulate calcium and phosphate absorption through intestinal brush border

1. increases sodium-phosphate transporters in enterocytes

2. increases epithelial calcium transporters

3. increases calbindins

major effect of vitamin D on the intestine

calbindins

Protein that transports Ca across osteoblasts to mineralizing (osteoid) side.

slightly increases reabsorption of filtered calcium and phosphate

affect of Vit D on kidney

interacts with osteoblast Vit. D receptors, causing increase in RANKL and M-CSF and hence resorption in the short-term

-BUT, increases availability of both Ca++ and Phosphate, so lots of substrate for mineralization during bone formation

affect of Vit D on Bone

calcitonin

works to lower plasma calcium, beginning only at calcium levels of 9.5 or higher

osteoclasts

what are the target cells of calcitonin

bind up osteoclasts to decrease bone resorption to decrease serum calcium

how does calcitonin target osteoclasts?

vitamin D

increases serum calcium and phosphate

calcium

affect of cortisol on ________:

-cause loss of calcium at the kidney

-reduces calcium absorption in the intestine

bone

long term effects of cortisol on ______:

-decrease bone formation during remodeling

-leads to OSTEOPOROSIS

increased bone turnover

increased alkaline phosphatase is a sign of

yes! due to the increased filtered load of calcium

does PTH increase calcium excretion?

primary hyperparathyroidism

which disorder:

-Elevated PTH!!! 

-stones, bones, groans, psychiatric overtones

-↑ serum [Ca²⁺] (hypercalcemia)

-↓ to normal serum [phosphate] (hypophosphatemia)

-↑ urinary phosphate excretion (phosphaturic effect of PTH)

-↑ urinary Ca²⁺ excretion (caused by the increased filtered load of Ca²⁺)

-↑ urinary cAMP

-↑ bone resorption

-Muscle weakness, constipation  etc

-decreased production of 1,25-dihyddroxycholecalciferol decreases calcium gut absorption

-kidney failure decreases calcium reabsorption

-causes increased PTH---> increased bone resorption and bone loss (osteomalacia)

-increased serum phosphate complexes free calcium, decreasing calcium

-calcification of arteries

affect of chronic renal failure on calcium and bones

Secondary hyperparathyroidism

high PTH, low calcium, high phosphate, VERY low vitamin D

tertiary hyperparathyroidism due to sustained secondary hyperparathyroidism

ESRD may also be called

tertiary hyperparathyroidism

very high PTH, high calcium, high phosphate, low/normal vitamin D

primary hypoparathyroidism

What disorder:

-often due to thyroid surgery (or congential)

-low PTH, low calcium and tetany , high serum phosphate, low urinary phosphate