Lecture 6: Regulation of Calcium and Phosphate Metabolism Flashcards
1
Q
What is the % distribution of total calcium among ECF, plasma, ICF, bones/teeth?
A
ECF: 0.1%
Plasma: <0.5%
ICF: 1%
Bones/teeth: 99%
2
Q
What is the biologically active form of calcium and what is its distribution?
A
Free, ionized Ca2+ is biologically active
Protein bound: 40%
Ultrafilterable: 60% —> Non-ionized complexed to anions (10%) and Ionized Ca2+ (50%)
3
Q
How do changes in the plasma calcium concentration influence membrane excitability, hypocaclemia and hypercalcemia?
A
Hypocalcemia: hyperreflexia, spontaneous twitching, muscle cramp, tingling and numbness
Hypercalcemia: decreased QT interval, constipation, lack of appetite, polyuria, polydipsia, muscle weakness, hyporeflexia, lethary, coma
4
Q
What are the two “signs” used to indicate hypocalcemic state?
A
Chvostek sign: twitching of the facial muscles elicited by tapping on the facial nerve
Trousseau sign: carpopedal spasm upon inflation of a blood pressure cuff
5
Q
How does Hypocalcemia influence the membrane excitability; affect on sensory and motor neurons?
A
- Reduces the activation threshold for Na+ channels -> easier to evoke AP
- Results in increased membrane excitability (spontaneous APs)
- Generation of spontaneous AP is the physical basis for hypocalcemic tetany (spontaneous muscle contractions due to low extracellular Ca2+)
- Produces: tingling and numbness (on sensory neurons) and spontaenous muscle twitches (on motorneurons and muscle)
6
Q
How does Hypercalcemia influence membrane excitiability?
A
- Opposite of hypocalcemia mechanism (decreased membrane excitability)
- Nervous system becomes depressed and reflex responses are slowed
7
Q
How do changes in plasma protein concentrations alter total Ca2+ concentrations?
A
- Alter total Ca2+ concentration in the same direction
- Increased plasma protein concentration = increased total Ca2+ concentration
- No change in Ca2+ ionized
8
Q
How do changes in anion concentrations alter total Ca2+ concentrations?
A
- If you increase anions, such as the phosphate concentration, you decrease the ionized Ca2+ concentration
- Anions will pick up the ionized Ca2+ increase the amount complexed in non-ionized form
9
Q
How does acidemia alter the ionized Ca2+ concentration?
A
- In acidemia there is more H+ which competes w/ Ca2+ for binding sites on albumin.
- Increased H+ will lead to an increase in free ionized Ca2+
10
Q
How does alkalemia alter the ionized Ca2+ concentration?
A
- Less H+ in the blood allows for more free ionized Ca2+ to bind to albumin
- This leads to a decrease in the amount of free ionized Ca2+ in the blood, often accompanied by hypocalcemia.
11
Q
What 3 organ systems and 3 hormones are involved in regulating calcium homeostasis?
A
Organs: kidney, bone, and intestine
Hormones: PTH, calcitonin, vitamin D (calcitriol)
12
Q
What hormone stimualtes the absorption of Calcium from the intestine?
A
Vitamin D
13
Q
What hormones have an affect on bone resorption?
A
Activators: PTH and Vitamin D
Inhibitors: Calcitonin
14
Q
How do the kidneys function to maintain Ca2+ balance; which hormone stimulates reabsorption of Ca2+ from the kidneys?
A
- Kidneys must excrete the same amount of Ca2+ that is absorbed by the GI tract
- PTH
15
Q
How is the extracellular concentration of phosphate related to that of Ca2+ and what hormones do the regulation?
A
- Extracellular concentration of Pi is regulated by the same hormones that regulate Ca2+ concentration
- Concentration of Pi is inversely related to that of Ca2+
16
Q
What is the % distribution of Pi in the bones, plasma, and ICF?
A
- Bone: 85%
- Plasma: <1%
- 84% ionized
- 10% protein bound
- 6% complexed
- ICF: 15%
17
Q
Where is the parathyroid gland located anatomically and what is secreted from here; specifically what cells?
A
- Posterior side of the thyroid gland
- Chief cells secrete PTH
18
Q
Describe the structure of PTH; where is it synthesized and how is it made into active form?
A
- Peptide hormone w/ 1-34th AA being biologically active
- Syntheszied on ribosomes as preproPTH then cleaved to form proPTH followed by transport to Golgi and further cleavage to form PTH before packed into secretory granules
19
Q
What are the 4 classic regulators of phosphate metabolism?
A
- Dietary phosphate intake and absorption.
- Calcitriol - increases phosphorus resorption from bone and absorption from intestine. Increases Pi reabsorption in kidney.
- PTH - phosphorus resorption directly from bone, and indirectly activates intestinal absorption through stimulation of calcitriol production.
- Renal tubular reabsorption of phosphorus, which is stimulated by tubular filtered
20
Q
What is FGF-23 and why it important in the regulation of phosphate concentrations in the plasma?
A
- Derived from bone
- Phosphate and Vitamin D levels regulated its expression, which in turns regulates phosphate homeostasis
21
Q
What are the 3 renal effects of FGF-23?
A
1) Directly downregulates NaPi transporters in kidney
2) Stimulates PTH to downregulate NaPi transporter in kidney
3) Decreases 1,25-dihydroxyD3 (calcitriol) produciton in the kidney
22
Q
What is the primary stimulus for the secretion of PTH?
A
Low plasma ionized Ca2+
23
Q
How is PTH production and secretion regulated by the parathyroid gland; how can it sense Ca2+ levels?
A
- Calcium-sensing receptor (CaSR)
- Hypercalcemia will causes downstream signaling to block PTH gene and block the release of PTH
- Hypocalcemia will stimulate PTH secretion
24
Q
How does 1,25-vitamin D have an effect on the parathyroid gland?
A
- Can cross the membrane into cells of parathyroid and either inhibit the PTH gene
- Can also upregulate the transcription of CaSR gene leading to increased CaSR’s on the surface of the cell membrane
25
What can mutations in the CaSR gene cause?
Familial hypocalciuric hypercalcemia (FHH)
26
How does chronic hypercalcemia affect PTH?
- Decrease synthesis and storage of PTH
- Increased breakdown of stored PTH and release of inactive PTH fragment into circulation
27
How does chronic hypocalcemia affect PTH?
- Increase synthesis and storage of PTH
- Hyperplasia of parathyroid glands (**2**° **hyperparathyroidism**)
28
How does Magnesium, especially severe hypomagnesemia affect PTH?
- Severe hypomagnesemia (result of chronic Mg2+ depletion, as in **alcoholism**)
- Inhibits PTH synthesis, storage, and secretion
29
PTH signals through which receptor and what pathways?
- GPCR
- Gs ----\> **cAMP** ----\> PKA
- Gq ----\> IP3/DAG -----\> increase Ca2+ and PKC
30
When plasma [Ca2+] is low and PTH secretion increases, what are the effects on bone, kidney, and intestine?
**Bone:** increased bone resorption
**Kidney:** decreased Pi reabsorption (phosphaturia), **increased Ca2+** reabsorption, and **increased urinary cAMP**
**Intestine:** increased Ca2+ absorption (**indirect via calcitriol)**
**\*ALL work towards increasing [Ca2+] toward normal**
31
Where does Vitamin D exert its actions and what are its functions?
- Has actions in: intestine, kidney, and bone
- Increases both [Ca2+] and [Pi] in plasma
- Promotes mineralization of new bone
32
What are the opposing effects of Vitamin D on Pi levels via action on kidneys and intestine?
- Can induce both FGF-23 and Klotho to i**ncrease urinary excretion** of **Pi** and lower serum phosphate levels
- **Increased** intestinal absorption of phosphate to **increase** serum [Pi]
33
What is the main circulating form of vitamin D and what needs to be done to make it active; what is the enzyme and where does the activation occur (be specific)?
- 25-OH-cholecalciferol is main circulating form (**inactive**)
- In **PROMXIMAL tubule of** **kidney** is converted to 1,25-dihydroxycholecalciferol (1,25-(OH)2-cholecalciferol) = **active**, by the enzyme **1**α-**hydroxylase**
- Can also be converted to, inactive, 24-25-(OH2)-cholecalciferol in te kidney by 24-hydroxylase
**\*1****α-hydroxylase = CYP1**α\*
34
What activates 1α-hydroxylase in the kidneys?
- Decreased [Ca2+]
- Increased PTH
- Decreased [Phosphate]
35
What form of Vitamin D do we ingest in our diets and then what happens in the body?
- Cholecalciferol (inactive)
- Converted in the **liver** to 25-OH-cholecalciferol (inactive form) by 25-hydroxlase
36
Explain how kidney 1α-hydroxylase is tightly regulated at the transcriptional level by 1,25-dihydroxyD, [Ca2+], and PTH?
- 1,25-dihydroxyD **inhibits** 1α-hydroxylase and sitmulates 24-hydroxylase expression
- High [Ca2+] **inhibits** 1α-hydroxylase expression
- PTH **stimulates** 1α-hydroxylase
37
Vitamin D is what kind of hormone and how does it assert its effects on a cell at a transcriptional level?
- **Steroid** hormone that binds a cytosolic and nuclear vitamin D receptor (VDR)
- In genomic response: binds to to nuclear VDR leading to **heterodimerization of the VDR w/ the retinoid X receptor (RXR**) and **binding** to vitamin D response element **(VDREs)** in the promoters of target genes affects transcription
38
Where are the PTH receptors in bone located and what are the short-term vs. long-term actions?
- On the **osteoblasts** NOT osteoclasts
**Short term:** bone formation (via direct action on osteoblast)
- Basis for use of intermittent synthetic PTH administration in osteoporosis tx
**Long term:** increased **bone resorption (**indirect action on osteoclasts mediated by cytokines released from osteoblast)
39
What are the actions of vitamin D on bone, specifically w/ PTH?
Acts synergistically w/ PTH to **stimulate** osteoclast activity and bone resorption
40
Explain the long-term action when PTH binds to osteoblasts, what are the key players (M-CSF, Vitamin D, RANKL, and RANK)?
- PTH binds to osteoblasts which secrecte **M-CSF,** inducing stem cells to differentiate into osteoclast precursors, mononuclear osteoclasts, and finally, mature, multinucleated osteoclasts.
- **Vitamin D** and **PTH promote** release of **RANK ligand**, which is a receptor activator for NF-kB ligand, and the **primary mediator** of osteoclast formation. RANKL binds to RANK on osteoclasts and osteoclast precursors
- Multi-nucleated osteoclasts are now able to facilitate bone resorption through the secretion of acids that breaks the osteoid
41
Explain how osteoblasts are able to put a break on the actions of osteoclasts, what are the key players (i.e., OPG)?
- Osteoblasts are also able to put a break on the system by producing a **decoy** receptor for RANKL, called **OPG,** which inhibits the RANKL/RANK interaction
- This short-term action will be **increased bone formation** via the actions of **osteoblasts**
42
What are the speicific actions of PTH and vitamin D on RANKL and OPG?
PTH: **increases RANKL and decreases OPG**
Vitamin D: **increases RANKL**
43
Where does RANKL come from?
Cell surface protein produced by: osteoblasts, bone lining cells and apoptotic osteocytes
44
How does PTH affect Pi reabsorption in the Proximal Tubule of the Kidney, which receptors/pathways?
- PTH binds its receptor at **basolateral membrane** of proximal tubule, which is coupled via **Gs** protein to **adenylyl cyclase**
- Adenylyl cyclase produces **cAMP**, which activates series of protein kinases, which then phosphorylate intracellular proteins
- Phosphorylation of the **luminal** Na+-Pi **(NPT)** co-transporter **inhibits** Na+-Pi co-transport leading to decreased Pi reabsorption and increased Pi excretion (**phosphaturia**)
45
Why is the cAMP produced during the binding of PTH to its receptors in the proximal tubule of the kidney significant?
cAMP generated in the cells of the proximal tubule is excreted in urine, and **urinary cAMP** can be measured to assess how the PTH system is functioning
46
What is the second renal action of PTH; where does it occur?
**- Increase** in **reabsorption** of **Ca2+** in the **DCT**
**-** Complements the increase in plasma [Ca2+] that resulted from **increased bone resorption** and **phosphaturia**
47
What are the actions of vitamin D on the kidney?
Stimulates **both** Ca2+ and Pi **reabsorption**
**\*Remember** that PTH increased reabsorption of Ca2+, but inhibits the reabsorption of Pi\*
48
What is the mechanism of action for Vitamin D on the intestine; what transporters does it induces synthesis of?
- Vit D induces the synthesis of an intracellular calcium-binding protein called **Calbindin**
- Induces synthesis of **Na-Pi transporter and Ca2+ channel** on the **luminal** side, needed for absorption of Pi and Ca2+
- Induces synthesis of the **Na+-Ca2+ antiporter** on the **basolateral** side
- Induces synthesis of the **Ca2+-ATPase** on the **basolateral** side
49
What sensitizes osteoblasts to PTH and regulates osteoid production and calcification?
Vitamin D
50
What organs does Calcitonin primarily act on; major stimulus; what are its functions?
- Bone and kidney
- Increased plasma [Ca2+] = major stimulus
- Decreases blood [Ca2+] and [Pi] by **inhibiting** bone resorption (effect **only occurs at high circulating levels** of the hormone)
- Promotes renal **excretion** of calcium and phosphate
51
Where are the calcitonin receptors found in bone and what are its actions here?
- On **osteoclasts**
- Decreases activity and decreases number of osteoclasts
52
What conditions prove that calcitonin has no role in chronic (minute-to-minute) regulation of plasma [Ca2+]?
**Thyroidectomy:** decreases calcitonin, but no effect in Ca2+ metabolism
**Thyroid tumors:** increased calcitonin, but no effect in Ca2+ metabolism
53
What effect does Estradiol-17β have on Ca2+ in the kidneys, intestines, and what are its effects on bone?
- Stimulates **intestinal Ca2+ absorption** and **renal tubular Ca2+ reabsorption**
- One of the most **potent regulators** of osteoblast and osteoclast function
- Promotes **survival of osteoblasts** and **apoptosis of osteoclasts**; favoring bone **formation \> resorption**
54
What effect do adrenal glucocorticoids (i.e., cortisol) have on bone and Ca2+; how does this affect patients treated w/ these drugs?
- Promotes bone resorption
- Promotes renal Ca2+ wasting
- Inhibits intestinal Ca2+ absorption
- Pt's tx w/ high levels of a glucocortcoid can develop **glucocorticoid-induced osteoporosis**
55
What is Primary hyperparathyroidism; normal treatment?
- Parathyroid problem resulting in **hypersecretion** of PTH
- Pt's excrete excessive amounts of Pi, cAMP, and Ca2+ = **Ca2+-oxalate stones**
- Increased GI Ca2+ absorption (mediated by Vit D)
- Increased renal calcium reabsorption
**- "Stone," "bones," and "groans"**
- Tx usually requires a **parathyroidectomy**
56
What is Secondary hyperparathyroidism; causes?
- Increase in PTH levels is secondary to low [Ca2+] in blood
- Causes for the low [Ca2+] in blood include:
- Renal failure
- Vit D deficiency
57
How do the levels of PTH, Ca2+, Pi, and vitamin D differ in secondary hyperparathyroidism due to renal failure vs. vitamin D deficiency?
58
What are the causes of hypoparathyroidism and what are most symptoms associated with; treatment?
- Thyroid surgery, Parathyroid surgery, and autoimmune/congenital
- Most sx's are associated w/ **decreased Ca2+**
- Muscle spasm/cramping, numbness, tingling, or burning around mouth and fingers, seizures, and poor teeth development in kids
- Tx: oral Ca2+ supplement and active form of Vit D
59
What are the levels of PTH, Ca2+, Pi, and Vit D in hypoparathyroidsim?
- Decreased PTH
- Decreased Ca2+
- Increased Pi
- Decreased Vit D
60
What is Albright hereditary osteodystrophy (pseudohypoparathyroidism type 1a)?
- Inherited autosomal dominant disorder; Gs for PTH in bone and kidney is defective
- Hypocalcemia and hypophosphatemia develop
- Increased PTH levels (but can't exert its function)
- Administration of exogenous PTH produces no phosphaturic response and no increase in urinary cAMP
61
What are the PTH, Ca2+, Pi, and Vit D levels in Pseudohypoparathyroidism?
- PTH is increased
- Ca2+ is decreased
- Pi is increased
- Vit D is decreased
62
What disease causes this phenotype?
- Pseudohypoparathyroidism
- Short stature, short neck, obesity, subcutaneous calcification, and shortened metatarsals and metacarpals
63
What is humoral hypercalcemia or malignancy; what is produced and how does it exert its effects?
- Hypercalcemic syndrome associated w/ malignancy
- PTH-related peptide (**PTHrP**) is a peptide produced by tumors w/ close homology in the N-terminal to PTH
- Binds and activates **same receptor** as **PTH** (type 1 PTH receptor)
64
What levels do we see in humoral hypercalcemia or malignancy; and how is it different from primary hyperparathyroidism?
Similarities:
- Increased urinary Ca2+, Pi, and cAMP
- Increased blood Ca2+, decreased blood Pi
Differences:
- Decreased PTH levels
- Decreased Vit D (in cancer, Vit D levels are normally suppressed)
65
What is the treatment for humoral hypercalcemia or malignancy?
- Furosemide (inhibits renal Ca2+ reabsorption and increases Ca2+ excretion)
- Etidronate (inhibitor of bone resorption)
66
What is Familial hypocalciuric hypercalcemia (FHH); inheritance pattern; results in?
- Autosomal dominant disorder
- Mutations that inactivate **CaSR** in parathyroid glands and paracellular Ca2+ receptors in the **ascending limb** of the kidney
- Results in decreased urinary Ca2+ excretion (hypocalciuria) and increased serum [Ca2+]
- Fairly mild condition and most patients are asymptomatic
67
What is the pathophysiology of Rickets-Osteomalacia?
Impaired Vit D metabolism:
- Dietary deficiency
- Absence of 1α-hydroxylase or mutations in Vit D receptor
- GI disorders, chronic renal failure, and Pi depletion can lead to pathophysiological changes in Vit D metbaolism
68
What are the 2 congenital disorders that can lead to Rickets in children?
1) Pseudovitamin D-deficientt rickets or vitamin D-dependent rickets **type I** (**decreased 1**α-**hydroxylase**)
2) Pseudovitamin D-deficientt rickets or vitamin D-dependent rickets **type II** (**decreased vitamin D receptor (VDR)**)
69
What are the characteristics of Osteomalacia?
- New bone fails to mineralize
- Characterized by bending and softening of weight-bearing bones
70
What are the treatments for Rickets-Osteomalacia?
- Vitamin D2 (ergocalciferol) or D3 (cholecalciferol)
- Ca2+
- Sunlight
- 1,25-(OH)2-D3 (calcitriol)
71
What are the levels of PTH, Ca2+ Pi, Urine, and Bone in Vitamin D deficiency?
- Increased PTH **(2°)**
- No change or decreased Ca2+
- Decreased Pi
- Increased urine Pi and cAMP
- Increased bone resorption
72
Why do women often experience Osteoporosis before men?
- After menopause women have very decreased levels of estrogen
- Estrogen is important for stimulating intestinal Ca2+ absorption and renal tubular reabsorption
- Estrogen is also one of the **most potent** regulators of osteoblast and osteoclast function; favoring **bone formation**
73
What are the anabolic therapies and antiresorptive therapies for Osteoporosis?
Anabolic:
- PTH
Antiresorptive:
- Bisphosphonates
- Estrogen
- Selective estrogen receptor modulators
- Calcitonin
- RANKL inhibitors
