Hormonal Control of Calcium and Phosphorus: Part 1 Flashcards by sophie rosen

Why are we Interested in

Calcium and Phosphorus? (3)

• Essential to many vital physiological processes
• Essential for proper mineralization of skeleton / dentition
• Disturbances in calcium
and phosphorus homeostasis linked to several
pathological disorders

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Why is it Important to Maintain Extracellular Calcium (Ca2+) within a narrow range?

Ca2+ ions critical to many cellular functions:
- Cell division / Cell adhesion
- Plasma membrane integrity
- 2nd messenger in signal transduction
- Muscle contractility
- Neuronal excitability
- Blood clotting
- Skeletal development
- Bone, dentin, enamel mineralization
Difficult to name a physiologic process not dependent on calcium

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Why is it Important to Maintain Phosphorus Homeostasis?

Phosphorus critical to many cellular functions:

Membrane composition (phospholipids)
Intracellular signaling
Nucleotide structure
Skeletal development
Bone, dentin, enamel mineralization
Chondrocyte differentiation

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3 major pools of calcium in body:

Bone calcium – 99%
Calcium in blood & extracellular fluid
Intracellular calcium

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Calcium in blood & extracellular fluid and intracellular calcium accounts for –% of calcium

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Adult body contains ~

1Kg calcium – 99% in
mineral phase of bone/teeth as hydroxyapatite
(HA) crystals

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HA mineralization of bone is important for

mechanical and weight bearing properties of bone

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Bone HA serves as reservoir of calcium to

maintain

blood ionized calcium within normal

range

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Normal range for total serum calcium =

8.5 – 10.5mg/dL (2.1-2.6mM)

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ionized (biologically active fraction)=

45%

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bound to albumin (pH dependent)=

45%

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complexed with citrate or phosphate ions=

10%

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Normal range of ionized calcium =

4.4-5.4mg/dL (1.1-1.35mM)

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Ionized calcium levels relatively stable but total

calcium can vary with changes in (2)

amounts of albumin

or pH, etc.

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In a typical individual:
~---mg calcium ingested per day
~---mg absorbed by gut
~---g filtered daily through kidney - most (~99%) is
reabsorbed
~---mg excreted in urine

1000
200
10
200

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—- stores about 1Kg calcium = major calcium

reservoir in the body

Skeleton

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~—mg/day calcium released from bone per day due
to normal bone turnover
~—mg/day deposited in bone due to bone formation

500

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Cells maintain — intracellular calcium concentrations in cytosol
what concentration?

low

~0.0001mM = 10-7M) (can increase 10-100 fold during calcium signaling, etc.

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Extracellular concentration much —

higher (~ 1mM = 10-3M)

~10,000x higher

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Maintenance of — gradient is important - intracellular calcium — regulate cell function

steep

fluxes

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Gradient achieved by — — in plasma membrane

Ca2+ pumps

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phosphorus is present as — — —- in solution

free phosphate ions

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Present as free phosphate ions in solution =

inorganic

phosphate (Pi) (mixture of HPO42- and H2PO4)

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Majority of body phosphate (~85%) in

hydroxyapatite

mineral phase of bone/teeth [Ca10(PO4)6(OH)2]

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Remainder of phosphate is distributed between

other tissues (14%) and extracellular fluid (1%)

Unlike calcium, phosphorus absorption in gut =

quite | efficient (~80-90% of dietary phosphorus absorbed)

Dietary deficiency in phosphorus is ---

uncommon

Adult serum Pi concentration ~

2. 5 to 4.5 mg/dL | 0. 8-1.5mM

Most extracellular phosphate is free in solution - | important buffer to maintain

physiological pH

Serum --- levels vary more than --- | as it is not as tightly regulated

phosphate | calcium

Amount of Ca2+/Pi ingested in food | = sum of amount lost in (2)

feces and | secrete hormones to excreted in urine

3 steps involved in calcium uptake

1. Uptake of calcium from apical side of cell - by ion channels belonging to TRP superfamily (Transient Receptor Potential ion channels) 2. Transcellular transport of calcium - by calcium binding proteins (calbindins) 3. Extrusion of calcium on basal surface of cell – by membrane transport proteins (Ca2+ ATPases or Na+ dependent Ca2+ exchangers)

Similar 3-step process occurs in gut, kidney, | osteoclasts, with

same groups of proteins but | specific isoforms are different

TRPV6 –

Ca2+ uptake on apical | side of intestinal epithelial cell

Calbindin D9K –

transcellular transport of Ca2+ to basal side of cell

Ca2+ATPase1b –

pumps Ca2+ out of basal side of cell (e.g. into capillary)

During high dietary calcium intake, --- also occurs

passive calcium uptake by a diffusional paracellular (between epithelial cells) path of absorption

Pi taken up into cell by

phosphate transporter - Na+ dependent Pi co-transporter type IIb (NaPi-IIb)– on brush border of ileum

Mechanism(s) for Pi --- transport/extrusion into circulation not yet known

transcellular

Also some Pi uptake by --- --- process

passive diffusion

After intestinal absorption into blood, Ca2+ and Pi is

filtered | in kidney glomerulus

~99% of Ca2+ and ~85-95% of Pi filtered in the kidney is

reabsorbed in kidney tubules (REABSORPTION = very | important)

Ca2+ uptake in renal reabsorption = same 3 step mechanism as in gut, but different

isoforms of TRP and calbindin

Ca2+ uptake in renal reabsorption 3 steps

1. Uptake - TRPV5 2. Transcellular transport – Calbindin D28K 3. Extrusion – Ca2+ ATPase 1b (PMCa1b), Na+ dependent Ca2+exchanger (NCX1)

Pi uptake in renal reabsorption – same mechanism as in gut | but different

isoforms of Na+ dependent Pi co-transporter | NaPi-IIa, NaPi-IIc

In osteoclasts most of calcium is transported through cell by --- into acidic vesicles followed by --- at cell surface

endocytosis | exocytosis

Many of the hormones involved in regulation of | calcium and phosphate homeostasis work by

altering expression of these key transporter molecules

Main Hormones/Regulatory Factors | Involved in Ca2+I Homeostasis (3)

Parathyroid Hormone (PTH) 1,25 dihydroxyvitamin D3 [1,25(OH)2D3] (calcitriol) Calcitonin (may play a more minor role)

Main Hormones/Regulatory Factors | Involved in Pi Homeostasis (3)

Parathyroid Hormone (PTH) 1,25 dihydroxyvitamin D3 [1,25(OH)2D3] (calcitriol) Fibroblast growth factor-23 (FGF23) (Dentin matrix protein-1/PHEX)

calcium and phosphate regulation is co-ordinated to some extent because

some of the regulatory molecules are the same (i.e. PTH and 1,25 (OH)2 D3) • E.g – calcium and phosphate are always released together during bone resorption

PTH has opposite effects on Ca2+ and Pi resorption in the

kidney

A couple of the hormones regulating Ca2+ and Pi homeostasis are different – for example (2)

calcitonin is released in response to high serum calcium and FGF23 is released in response to high serum phosphate

--- molecules responsible for Ca2+ and Pi uptake are different

Transport

while the system allows for some coordination it also | allows for Ca 2+ and Pi to be regulated --- if needed

independently

--- homeostasis more fully understood than --- | homeostasis

Calcium | phosphate

Serum calcium concentrations detected by | --- expressed in parathyroid gland

Calcium Sensing Receptor (CaSR)

increase Serum Ca2+ = --- CasR signaling = --- PTH secretion

increase | decrease

decrease Serum Ca2+ = --- CasR signaling = --- PTH secretion

decrease | increase

PTH is an 84 a.a. peptide hormone produce by

parathyroid glands

Calcium regulatory activity of PTH confined to first --- a.a.

half life of PTH

~5 min | short half life

PTH receptor

PTH1R (also binds PTHrP [parathyroid hormone related | peptide])

Class of PTH receptor

B G-protein coupled receptor

PTH actions mediated via activation of

adenylate | cyclase/cAMP production

Low serum Ca2+ levels results in

CaSR signaling shut off which leads to | release of PTH

PTH Actions: (3)

• Increases bone resorption - i.e. releases calcium and phosphate • Increases calcium reabsorption in kidney • Opposite effect on phosphate reabsorption in kidney (reduces Pi reabsorption -can lead to phosphaturia)

In kidney - PTH stimulates conversion of 25-hydroxyvitamin D3 [25(OH)D3] to

active form 1,25-dihydroxyvitamin D3 | [1,25(OH)2D3]

1,25 dihydroxyvitamin D3 induces expression of

Calbindins and other components of calcium transport system (TRPV5, TRPV6, Ca2+ ATPases, Na+/Ca2+ exchangers) –

1,25 dihydroxyvitamin D3 Induces expression of Calbindins and other components of calcium transport system (TRPV5, TRPV6, Ca2+ ATPases, Na+/Ca2+ exchangers) – resulting in increased: (3)

Ca2+ uptake in the intestine Ca2+ reabsorption in the kidney tubules Ca2+ release into circulation from bone

1,25 dihydroxyvitamin D3 induces expression of phosphate transporters (NaPi-IIa,NaPi-IIb,NaPi-IIc) – resulting in increased: (3)

Pi uptake in the intestine Pi reabsorption in the kidney tubules Pi release into circulation from bone

1,25 dihydroxyvitamin D3 feeds back to inhibit

further production of PTH (negative feedback)

Combined actions of PTH and 1,25(OH)2D3 → =

increase serum calcium (and phosphate) back to | normal range

Further production of PTH inhibited when Ca2+ | returns to normal and also because of inhibition by

1,25(OH)2D3 (NEGATIVE FEEDBACK LOOP)

Opposite sequence of events happens when serum | calcium is ---

HIGH

CaSR signaling activated which reduces

PTH secretion

Resultant reduction in --- production in kidney

1,25(OH)2D3

Leads to --- release of calcium and phosphate from skeleton, --- intestinal calcium and phosphate absorption/renal calcium reabsorption

reduced | reduced

Many of effects mediated through modulation of | expression of

calcium transporter proteins

Calcitonin = hormone released by --- gland in | response to --- serum calcium

thyroid | elevated

Calcitonin generally opposed --- actions

PTH

Major effect of calcitonin-

inhibits osteoclast resorption in bone by causing retraction of osteoclast ruffled border

Minor effect of calcitonin

inhibits renal reabsorption of Ca2+ and phosphate allowing them to be excreted in the urine

Calcitonin role now thought to play a more minor role because

thyroid tumors that secrete excessive amounts of calcitonin have normal serum calcium (probably kidneys become resistant)

Removal of thyroid has only a small effect on

calcium homeostasis

Main regulators of phosphate homeostasis: (4)

Parathyroid hormone (PTH) 1,25-dihydroxyvitamin-D3 [1,25(OH2)D3] Fibroblast growth factor 23 (FGF23) (Dentin matrix protein-1/PHEX)

Parathyroid hormone (PTH) - -- phosphate release from bone - -- renal phosphate reabsorbtion - -- 1,25 D3 production by kidney

increases decreases increases

1,25-dihydroxyvitamin-D3 [1,25(OH2)D3] | increases (3)

phosphate release from bone, increases renal phosphate reabsorption, phosphate uptake in gut

Regulation overlaps with regulation of Ca2+ but also | ---

independent

Phosphate regulation not as well understood as calcium – | --- evolving field

rapidly

--- sensing mechanism not yet determined

Phosphate

FGF23 -- kDa protein – important in --- regulation

32 | phosphate

Expression induced in bone when --- --- too high (esp. osteoblasts, osteocytes, lining cells/ osteoprogenitors)

serum phosphate

FGF23 can be cleaved into smaller fragments of 12 and 20kDa to

inactivate the protein

Expression of FGF23 in osteocytes inhibited by two key proteins:

Dentin matrix protein-1 (DMP1) | Phosphate regulating endopeptidase homolog, X-linked (PHEX)

major source of endocrine FGF23 and now known to | be major players in regulation of phosphate homeostasis

osteocytes

FGF23 Actions in the Kidney: (2)

• Decreases reabsorption of phosphate (by downregulating expression of Na+ dependent phosphate transporters) – means that more phosphate is excreted in urine. • Decreases production of 1,25(OH)2D3

Overall effect of FGF23 –

lowers serum phosphate

Although gut and skeleton contribute to phosphate regulation, main mechanism for (rapid) regulation of phosphate –

KIDNEY reabsorption

Type II Na2+-dependent phosphate co-transporters | expressed in proximal tubules = (2)

NaPiIIa, NaPiIIc

PTH inhibits

``` phosphate reabsorption (via inhibition of NaPiIIa and NaPiIIc expression) ```

Absence of PTH increases

phosphate reabsorption

FGF23 produced by osteocytes when serum phosphate is | high -

downregulates NaPiIIa and NaPiIIc (reduces Pi | reabsorption in kidney)

Factors Regulating Calcium and Phosphate Homeostasis (4)

PTH 1,25 (OH)2D3 (calcitriol) Calcitonin FGF23

System has some overlap - especially bone resorptive component, because

Ca and Pi are simultaneously released during resorption

Because the renal reabsorption of Ca and Pi are regulated | differently by PTH, and because FGF23 regulates phosphate separately, this allows some degree of

independent regulation