Ca And P Homeostasis Flashcards
Cation with the highest concentration in the body? Where is it stored?
Ca2+
>99% of the body calcium is in the skeleton and other 1% is in other tissues and body fluids
Phosphorus
- T or F. It is present in every cell of the body.
- Location of storage?
- True!
2. 80% in the skeleton and 20% in other tissues and body fluids
The levels of Ca2+ and PO34- is regulated by 3 things:
- GI absorption and secretion (actually, more of absorption)
- Kidneys would also play a role in your Ca and P lvl (can inc or dec the reabs rate of Ca and P)
- Bone turnover wherein you have your bone formation (w/c lowers down Ca and P blood lvl) and bone resorption (break down bone increasing your Ca and P lvl)
Forms of Ca and P in the body?
Both Ca and P would exist in 3 forms:
1. Ionized/free (50%)
Majority of Ca2+ in the blood would exist in the ionized form. Impt bc this form is the active form or is the one responsible for the physiologic effects of Ca2+
IMPORTANT!!!
- Complexed
Remaining 10%
Complexed -> meaning Ca that is bound to other anions (e.g. PO4, SO4, HCO3, etc) - Protein bound (40%)
2nd most high conc
This is the form of Ca that is bound to your plasma proteins (most impt one is your albumin)
Effect of the ff on Calcium levels:
- Hypoalbuminemia
- Acidemia
- Hyperalbuminemia
- Alkalemia
Conditions that can inc or dec your Ca2+ lvls
-Hypoalbuminemia (low lvls of albumin)
>protein bound Ca will dec and a concomitant effect of that is your free Ca would increase
>same is true for acidemia or acidosis (inc lvl of protons and these protons would displace your Ca2+ that is bound to your albumin) so as a result, your ionized Ca2+ would inc
Hyperalbuminemia
>If you have lots of albumin, Albumin will take Ca, lowering free ionized Ca
>same as alkalemia (dec protons on your blood causing more of free sites on Albumin where Ca can bind into so tataas si protein bound Ca)
What are calcitriopic hormones?
- PTH
2. 1,25-hydroxyvitamin D (Calcitriol)
T or F. Calcitonin is a calcitripic hormones?
F! It is also involved on calcium homeostasis but works opposite to the calcitriopic leading to lowering down Ca2+ lvl.
How do calcitriopic hormones maintain body Ca2+? P?
How our body maintains Ca2+
Note: PTH and Calcitriol, they would inc plasma Ca2+ lvl by
1. Inc bone resorption (facilitate the break down of your bone freeing up your Ca2+)
2. At the same time, at the lvl of kidneys, PTH and Calcitriol would inhibit the excretion of Ca2+ (or in other words, it inc reabs of ca2+)
3. At the lvl of small intestines, it’s only calcitriol that would exert its effect not PTH (so what happens, you inc the absorption of Ca2+)
For P:
1. Sa bones, both PTH and Calcitriol would still inc bone resorption thereby inc your plasma P lvl
2. At the lvl of kidneys, they would have opposing effects
>Si PTH would inhibit reabsorption at lvl of PCT (so it inc the excretion) and your calcitriol would inhibit excretion so opposing fx BUT between the 2, PTH would have greater effect than calcitriol so net effect of PTH is you inc P excretion even tho vit D is present
3. At lvl of small int, calcitriol would inc P absorption in the GIT
- Primary hormones that would prevent hypocalcemia?
- What secretes #1?
- Main sites of action of #1?
- Feedback on Vitamin D?
Parathyroid hormone
- secreted by your gland (so it is located on the post aspect of thyroid gland)
- specifically, it would be the principal/chief cells that would secrete your PTH
- described as the primary hormone that would prevent hypocalcemia so it would inc your serum Ca2+ lvl
- main sites of PTH action: kidneys and the bones (not the GI Tract)
- (+) production of Vitamin D
Secretion and Regulation of PTH
One of the fx of PTH, inc synthesis of Vitamin D
This is the secretion of PTH by your chief cells
- At the surface/PM of your chief cell, you have CSR (Ca-sensing receptor) receptor that detects Ca2+ lvl
- At low lvls/absence of Ca2+, the receptor will not be activated so PTH will be secreted or exocytosed
- But if we have increasing lvls of Ca, Ca2+ now will activate the receptor -> cascade of events which inhibits exocytosis of PTH (so PTH secretion dec when u have high lvls of Ca2+)
Half life of PTH?
2 minutes
T or F. PTH is a steroid hormone.
F!! Peptide hormone.
Relationship between serum PTH and PTH secretion/Free Ca2+ in the blood
Sigmoidal but inverse
Higher serum PTH -> lower Ca2+ in the blood/lower %PTH secretion
PTH receptor
>Where are these located?
>Effect
> PTHr
PTHrP
Parathyroid hormone-related peptide (may binding site)
expressed by kidneys and bones
Effect: Increase plasma Ca2+ lvls
Note: At the lvl of kidneys, you increase Vitamin D synthesis (specifically at the PCT)
Vitamin D! >Type of hormone >Precursor >Synthesized as? Where? >Function >Forms we get from diet
Vit D
-another calcitriopic hormone; steroid hormone
-precursor: 7-dehydocholesterol
-The Vit D we know is a prohormone (inactive). Once in our body, it will be conv to 1,25-dihydroxyvitamin D (aka 1,25-dihydroxycholecalciferol or Calcitriol)
-The precursor is synthesized in the basal layers of the skin
-Function: would target small int, kidneys, and bone
-The forms of Vit D we get from our diet, there are 2: Ergocal and Cholecal
>Plant source and the other one is animal source
Vitamin D synthesis?
> 7DHC sa skin to, once this is acted upon by UV rays/light what happens is this ring will open forming your cholecalciferol -> cholcal will be transported to the liver (so Vit D3 - liver)
same is true for dietary Vit D3 we get (once absorbed, it will utimately be transported to liver as well)
In the liver you have 25-hydroxylase which will hydroxylate your cholecal forming now your 25-hydroxycholecalciferol (this is still an inactive hormone). What will activate it is an enzyme found on your PCT sa kidneys (1-alpha hydroxylase, after action you get 1,25-Dihydroxyvitamin D (active hormone) -> you now have physiologic/biologic fx
There’s another pathway:
- Which forms your 24,25-Hydroxylase
- So your enzyme is 24-hydroxylase (a pathway that inactivates Vit D)
Regulation of Vitamin D.
1. 24-hydroxylase
- PTH
- FGF-23
> Vit D exerts negative feedback by increasing synthesis of 24-hydroxylase which will exert a positive feedback on itself. This enzyme inactivates Vitamin D.
> Binding of PTH to the receptor increases transcription of 1-alpha-hydroxylase so you’ll form more of active Vitamin D. Vitamin D would exert a negative effect by inhibiting transcription of 1-alpha-hydroxylase so di over effect.
> FGF-23 is a hormone produced by osteocytes in the bone. One of its effect is to inhibit 1-alpha-hydroxylase synthesis.
Vitamin D receptor
-Location
Vit D receptor
- Vit D being a steroidal hormone is nonpolar so it can readily diffuse in the cell so its receptor is intracellular specifically for Vit D, a nuclear receptor (parang thyroid hormone)a
- Vit D readily diffuses in nucleus and binds to NRs -> hormone + receptor complex will bind to specifc areas in DNA where it can inhibit/activate gene transcription resulting to the ff effects: Apoptosis, Anti-angiogenesis, differentiation, cell cycle arrest
Which of these 3 hormones has an effect on your GI Tract - PTH, Calcitriol, or Calcitonin? How?
Epithelial Ca channels: TRPV5 & 6
Basolateral: PMCA or Na/Ca exchanger
NPT2Slide
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-Which of the 3 hormones has an effect on your GI Tract - PTH, Calcitriol, or Calcitonin? Calcitriol (Vit D lang) TATANUNGIN NIYA TO SA QUIZ HAHAHA
-Vit D increases the absorption of Ca and P
How? It would inc synthesis of the proteins necessary for absorption of these 2 ions
What are those transporters or proteins? Channels on the apical side (TRPV5/6), Calbindin (Calcium binding protein), and it would inc synthesis of proteins located in the basolateral membrane (Na/Ca exchanger: NCX), Ca ATPase (PMCA: Plasma Membrane Ca2+ ATPase)
For Phosphate, ganun din. Vit D would inc synthesis of proteins necessary for absorption of Phosphate:
>On apical side: Na/P symporter
>Basolateral side: Na/K pump, Phosphate transporter (yung question mark)
So the net effect of Vit D -> inc Ca and P absorption
Renal handling of Ca2+ and Pi?
This slide is the summary of the fx of PTH and Vit D in the kidneys.
Note: PTH has 2 fx for Ca2+
>At lvl of PCT, PTH would decrease Ca2+ reabsorption.
>At lvl of thick ascending limb and DCT, PTH would inc Ca2+ reabs
-Bet the 2, the predominant effect of PTH would be sa DCT
>In terms of Phosphate, your PTH would dec P reabs at PCT and it would also inc Vit D synthesis at PCT
Vit D
- has opposing effects to PTH (2 fx pala)
- In terms of Ca2+ reabs, it is synergistic w/ PTH (same fx: reabs)
- For Phosphate, opposing. Vit Di will enhance P reabs while DCT would dec. Bet the two, PTH would have a greater effect on your P reabsorption
What is bone turnover?
Cyclic process of bone destruction (bone resorption) and bone deposition (new synthesis of bone matrix)
How does bone resorption occur?
RANK: Receptor for activation of nuclear factor κB
OPGRANK: Receptor for activation of nuclear factor κB
OPG
-
Let’s start first w/ bone resorption
>What’s impt here is that your PTH hormone and Vit D would only exert their effect on osteoblast (your osteoblast would express receptor for PTH and Vit D. Not osteocyte nor osteoclast)
>So high lvls of Vit D sensitizes your osteoblast for your PTH (meaning mas nagiging sensitive siya for PTH) meaning to say, at lower amts of PTH, your PTH could bind to its receptor kay osteoblast
>Yun ginagawa ni Vit D (sensitizes your osteoblast for your PTH)
-Si PTH naman (high lvls) when it binds to your osteoblast would secrete several factors:
1. M-CSF (Monocyte-Colony Stimulating Factor) which causes the differentiation of your stem cell. Your SCs would become/dx into preosteoclast or osteoclast precursors which are special cells that would express receptors for 2 ligands: (a) IL-6 receptor and (b) RANK (receptor for activator of NFkB)
2. IL-6
3. RANKL (RANK Ligand)
Meaning to say these 2 would bind to their respective receptors. When your IL-6 and RANKL bind to their receptor, your preosteoclast would now dx into your multinucleated osteoclast. This multinucleated osteoclast is the mature osteoclast/the one that can perform its fxn which is bone resorption)
> So in other words, PTH and Vit D would indirectly promote formation of multinucleated osteoclast -> hence, bone resorption
> At low lvls of PTH, when PTH binds to the osteoblast, your osteoblast would secrete OPG (Osteoprotegerin: osteo = bone; protect), a factor that sequesters your ligand for RANK so that RANKL would not bind to RANK. So OPG will protect the bone from being resorbed
- Osteoclast in the presence of RANKL would do the ff things:
1. Activate proton pump (Pump out H+ ion into space and at the same time, pump out Cl ion so you now form HCl)
2. Cause the exocytosis of lysosomes such that the lysosomal enzyme will now be present inside the space
3. HCl + lysosomal enzymes will break down the matrix of the bone, freeing up the Ca2+ and P so nasisira siya
Bone Mineralization
On the other side, your bone deposition (fxn of osteoblast) or Bone mineralization
-So your osteoblast would initially form an osteoid. It will release certain factors surrounding this area.
Factors: Pyrophosphate, AP, GPs. All of which would take Ca2+ and P from the blood and form your mineralized bone so magfform yan ng osteoid dito.
- Eventually osteoblast will be surrounded by mineralized bone. Once it is surrounded, it will now become an osteocyte so si osteocyte wala na siya effect on bone deposition or bone resorption
- Other factors that would increase your bone mineralization would be your mechanical stress but recent studies show that the presence of microfractures on the bone would cause the osteocytes to secrete a hormone, osteocalcin, w/c promotes bone deposition. (PERO WALA PA SA BOOK SO MECH STRESS NA LANG MUNA)
Effect of Calciotropic Hormones on bones?
PTH
- 1’ regulator of bone remodeling in adults
- PTH/PTHrP receptor is found in osteoblasts ONLY
- indirectly activates osteoclasts
Vitamin D
- sensitizes osteoblasts for PTH
- For coordination of osteoid production & calcification
- VDr is found in osteoblasts ONLY
- increases serum Ca2+/PO43- (eventually bone deposition)
