Hormonal Control of Ca and P Flashcards
(a.k.a. 1,25(OH)2D3) the active form of vitamin D.
Calcitriol
a fancy word for elevated levels of calcium in the urine
Hypercalciuria
a fancy word for elevated levels of phosphate in the urine
Hyperphosphaturia
a fancy word for high levels of calcium in the circulation that exceed the normal range
Hypercalcemia
abnormally low levels of calcium in the circulation that are below the normal range
Hypocalcemia
high levels of phosphate in the circulation that exceed the normal range
Hyperphosphatemia
low levels of phosphate in the circulation that are below the normal range.
Hypophosphatemia
a condition in which there is excess parathyroid hormone in the circulation
Hyperparathyroidism
a condition in which the parathyroid secretes abnormally low levels of PTH
Hypoparathyroidism
a condition with a biochemistry similar to hypoparathyroidism (i.e. low serum calcium and high phosphate), but in which PTH levels are normal or high. The condition is due to resistance to PTH in the target tissues due to mutations in G-protein signaling molecules important for PTH signaling.
Pseudohypoparathyroidism
a disease in which the bone does not mineralize properly. Characterized by unmineralized osteoid seams that are wider than in normal individuals.
Osteomalacia
a disease resulting from low serum calcium and phosphate in children, which leads to weakened undermineralized bones and abnormalities in the cartilage growth plate. Symptoms include growth retardation, weakened bones/bowing of the legs.
Rickets
- Cell division / Cell adhesion - Plasma membrane integrity
- 2nd messenger in signal transduction - Muscle contractility - Neuronal excitability - Blood clotting - Skeletal development - Bone, dentin, enamel mineralization
Critical cellular functions of CA2+
what are the three major pools of calcium in the body?
bone, blood/ extracellular fluid, and intracellular fluid.
Bone ____ serves as a reservoir of calcium to maintain blood ionized calcium within normal
range
Hydroxyapatite (HA)
What is the mineral phase of calcium??
hydroxyapatite
Normal range for total serum calcium
8.5 – 10.5mg/dL (2.1-2.6mM)
Normal range of ionized calcium
- 4-5.4mg/dL (1.1-
1. 35mM)
Ionized calcium levels relatively stable but total
calcium can vary with changes in amounts of _______
or______ , etc
Albumin and pH
What is the major calcium reservoir in the body? How much calcium does it store??
bones: 1 kg of calcium.
What is the biologically active fraction of serum calcium
Ionized
45% of total serum calcium
What is the pH dependent fraction of serum calcium?
Calcium that is bound to albumin which is 45% of total serum calcium.
the _______ concentration of calcium is greater.
Extracellular concentration
________ concentration of calcium is much lower than ________ concentration
Intracellular
Extracellular
What maintains the intercellular and extracellular concentrations of calcium
Ca2+ pumps
- Membrane composition (phospholipids)
- Intracellular signaling
- Nucleotide structure
- Skeletal development
- Bone, dentin, enamel mineralization
- Chondrocyte differentiation
Phosphorus cellular functions:
The majority of both Calcium and Phosphorus are located in which compund?
hydroxyapatite
Unlike calcium, phosphorus absorption in______ = quite
efficient (~80-90% of dietary phosphorus absorbed).
GUT
Adult serum Pi concentration
- 5 to 4.5 mg/dL
0. 8-1.5mM
_______ is an important buffer to maintain physiological pH.
Phosphorus
T or F: Phosphorus is more tightly regulated than calcium.
FALSE
Which organ secretes hormones that regulate Ca2+ and Pi uptake/ release in bone, kidneys, and in the gut.
Parathyroids
_____ is a superfamily of ion channels that uptake calcium on the apical side of the cell.
(TRP) Transient
Receptor Potential ion channels
_____ is a superfamily of ion channels that uptake calcium on the apical side of the cell.
(TRP) Transient
Receptor Potential ion channels.
_______ are responsible for transcellular transport of calcium.
calbindins
Calcium binding proteins.
___________ of calcium on basal surface of cell – by
membrane transport proteins (Ca2+ ATPases or Na+
dependent Ca2+ exchangers)
Extrusion
What are the three steps of calcium uptake?
TRP uptake
Transcellular transport of calcium
Extrusion
Similar 3-step process occurs in gut, kidney,
osteoclasts, with same groups of proteins but
specific isoforms are different
What are the three step iosforms for calcium uptake in the gut?
TRPV6
Calbindin D9K
Ca2+ATPase1b
Pi taken up into cell by phosphate transporter - Na+ dependent Pi co-transporter type IIb (NaPi-IIb)–
on brush border of ileum
Phosphate (Pi) Uptake in the Gut
Also some Pi uptake by _____ ______ process
Passive Diffusion
about ____% of Calcium and about ____% of Pi is reabsorbed in the glomerus of the kidney?
99%
85-95%
Step one of calcium uptake utilizes ___ for Ca2+ uptake on apical side of intestinal epithelial cell
(TRP) Transient
Receptor Potential ion channels.
Step one of calcium uptake utilizes _____ for transcellular transport of Ca2+ to basal side of cell.
Calbindin
Step three of calcium uptake utilizes __ _____ for pumps Ca2+ out of basal side of cell (e.g. into capillary)
Ca2+ATPase1b
What are three hormones involved in Calcium regulation?
Parathyroid Hormone (PTH)
1,25 dihydroxyvitamin D3 [1,25(OH)2D3] (calcitriol)
Calcitonin (now thought to play a more minor role)
What are three hormones involved in Phosphorus regulation?
Parathyroid Hormone (PTH)
1,25 dihydroxyvitamin D3 [1,25(OH)2D3] (calcitriol)
Fibroblast growth factor-23 (FGF23) (osteocytes)
______ has opposite effects on Ca2+ and Pi resorption in the kidney.
PTH
_______ is released in response to high serum calcium
calcitonin
________ is released in response to high serum phosphate
FGF23
Transport molecules responsible for Ca2+ and Pi uptake are different which results in …….
independent regulation of calcium and phosphate.
Serum calcium concentrations detected by ____ ____ ____ expressed
in parathyroid gland
Calcium Sensing Receptor (CaSR)
↑Serum Ca2+ ↑CasR signaling =
↓PTH secretion
↓Serum Ca2+ ↓CasR signaling =
↑PTH secretion
• 84 a.a. peptide hormone produce by parathyroid glands • Calcium regulatory activity confined to first 34 a.a. • Short half-life = ~5 minutes
PTH
What is the PTH receptor?
it is PTH1R
- Increases bone resorption - i.e. releases calcium and phosphate
- Increases calcium reabsorption in kidney
- Opposite effect on phosphate reabsorption in kidney
Actions of PTH
In kidney -_____ stimulates conversion of 25-hydroxyvitamin D3
[25(OH)D3] to active form 1,25-dihydroxyvitamin D3 [1,25(OH)2D3]
PTH
Induces expression of Calbindins and other components of
calcium transport system (TRPV5, TRPV6, Ca2+ ATPases, Na+/Ca2+ exchangers)
resulting in increased:
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:
Pi uptake in the intestine
Pi reabsorption in the kidney tubules
Pi release into circulation from bone
1,25 dihydroxyvitamin D3
Opposite sequence of events happens when serum calcium is HIGH
Negative feedback loop.
- CaSR signaling activated – reduces PTH secretion
- Resultant reduction in 1,25(OH)2D3 production in kidney
- Leads to reduced release of calcium from skeleton, reduced intestinal calcium absorption/renal calcium
reabsorption
What gland releases Calcitonin?
thyroid gland
_______ opposes PTH actions
Calcitonin.
______ acts on calcitonin receptor (CTR) in
osteoclasts - activation causes retraction of osteoclast ruffled border
Calcitonin
______ ____ ____ expression induced in bone when serum phosphate too
high (esp. osteoblasts, osteocytes, lining cells/ osteoprogenitors)
Fibroblast Growth Factor 23 (FGF 23)
Fibroblast Growth Factor 23 (FGF 23) expression in osteocytes is inhibited by what two key proteins?
Dentin matrix protein-1 (DMP1) Phosphate regulating endopeptidase homolog, X-linked (PHEX)
What is the role of FGF23 in the Kidney?
lowers serum phosphate.
main mechanism for (rapid) regulation of
phosphate =
KIDNEY reabsorption
What role do NaPiIIa, NaPiIIc have in phosphate regulation?
Ty p e II Na2+-dependent phosphate co-transporters
expressed in proximal tubules
_______ produced by osteocytes when serum phosphate is
high - downregulates NaPiIIa and NaPiIIc (reduces Pi
reabsorption in kidney)
FGF23
↑serum Ca2+ ↓serum Pi
PTH
↑serum Ca2+ ↑serum Pi
1,25 (OH)2D3 (calcitriol):
↓serum Ca2+
Calcitonin:
↓serum Pi
FGF23:
affects Ca2+ /Pi homeostasis because
impaired kidney function interferes with Ca2+ and Pi reabsorption
Chronic kidney disease -
blood calcium concentration
below normal range (<1.1-1.35 mM ionized calcium)
Hypocalcemia
What are some symptoms of Hypocalcemia?
- Muscle cramping
- Increased neuromuscular excitability
- Muscle spasms
- Fatigue
- Cardiac dysfunction
- Depression, psychosis, seizures.
What are some causes of Hypocalcemia?
PTH resistance, Inadequate vit. D, PTH and Vit D insuffiencicy .
undersecretion of PTH
Hypoparathyroidism
CaSR signals constitutively even though Ca2+ levels are low (i.e. parathyroid “misreads” Ca2+ levels as high and inappropriately suppresses PTH)
Hypoparathyroidism Associated with Activating CaSR Mutations (Autosomal dominant hypocalcemia - ADH)
(Insensitivity to PTH)
A type of Hypocalcemia due not to the lack of PTH but due to lack of responsiveness of target tissues to PTH.
This is due to mutations in G proteins important for PTH signaling.
Pseudohypoparathyroidism
_______ causes more hypocalcemia than hypoparathyroidism.
Lack of vitamin D inhibits Ca2+ and Pi uptake in gut (due to
downregulation of calcium and phosphate transport proteins,
Calbindins, TRPV6, NaPi-IIb)
Vitamin D Deficiency
Vitamin D Deficiency can lead to ______ in growing children.
Ricketts
Vitamin D Deficiency can lead to ______ in adults.
osteomalacia
pseudovitamin D deficiency rickets
- AR inheritance
- Defect in renal 25-OH-vitamin D-1α-hydroxylase
- Low serum Ca2+, Pi
- High PTH
- Very low 1,25(OH)2D3
VDDR Type I
Vitamin D- Dependent Ricketts
hereditary vitamin D resistant rickets
There is Elevated 1,25(OH)2D3 but a defect in the Vit D receptor. results in high PTH and low Ca and Pi
VDDR type II
a.k.a. hereditary vitamin D resistant rickets
blood calcium concentration
higher than normal range (>1.1-1.35mM ionized)
Hypercalcemia
What are some symptoms of hypercalcemia
• Fatigue • Electrocardiogram abnormalities • Nausea, vomiting, constipation • Anorexia • Abdominal pain • Hypercalciuria/kidney stone formation • Calcification of soft tissues – (e.g. vasculature).
What are two of the many causes of hypercalcemia
Elevated PTH levels and Elevated 1,25 (OH)2D3 levels
Usually, 1 of 4 parathyroid glands makes too much PTH due to development of benign adenoma resulting in excessive PTH synthesis/secretion (85% of cases)
Primary Hyperparathyroidism (PHPT)
What are they two types of Familial Primary Hyperparathyroidism (Inherited forms)
Multiple Endocrine Neoplasia (MEN) type 1 and 2a.
hyperparathyroidism due to inactivation of tumor suppressor gene Menin (gene name MEN, One copy of gene is mutated, but “second hit” needed for tumor formation
MEN1
Multiple Endocrine Neoplasia (MEN) type 1
Hyperparathyroidism Due to gain of function mutation in RET protooncogene
MEN 2A
Multiple Endocrine Neoplasia (MEN) type 2A
__________ for inactive CaSR have familial
hypocalciuric hypercalcemia where CaSR doesn’t signal even though Ca2+ levels are high (i.e. parathyroid misreads Ca2+ levels as being low) therefore PTH is inappropriately elevated
Heterozygotes for Inactivating mutations of CaSR in relation to Familial Primary Hyperparathyroidism
_________ have neonatal severe hyperparathyroidism
(NSHPT) – potentially fatal - requires parathyroidectomy
Homozygotes for Inactivating mutations of CaSR in relation to Familial Primary Hyperparathyroidism
Some cancers, e.g. squamous
carcinomas, some breast cancers,
secrete PTHrP - mimics PTH actions
Hypercalcemia of Malignancy
View the summary pages of Both Diseases of Hyper calcemia and Hypocalcemia.
It condenses everything down.
Oversecretion of PTH in response to conditions of
hypocalcemia and/or decreased 1,25(OH)2D3
Secondary Hyperparathyroidism
not actually a condition of hypercalcemia
Phosphate levels lower than normal (<0.8-1.5mM)
Hypophosphatemia
Causes of Hypophosphatemia
Decreased intestinal absorption of phosphate
Increased urinary
excretion
Redistribution from extracellular fluid into cells/tissues
Most common disorder of renal phosphate wasting due to mutations in PHEX gene on X-chromosome (phosphate- regulating gene with homologies to endopeptidases on the X chromosome)
X-linked Hypophosphatemic Rickets (XLH)
What is the mechanism of XLH (X-linked Hypophosphatemic Rickets)
PHEX produced by osteoblasts, osteocytes, odontoblasts
• PHEX normally inhibits FGF23 production
• XLH mutations of PHEX lead to inappropriately elevated
FGF23 production, even though serum phosphate is low.
FGF23 reduces renal reabsorption of phosphate (leads to
renal phosphate wasting - i.e. more excreted in urine)
Rare form of inherited hypophosphatemic rickets Due to mutations in FGF23 that alter cleavage site so it cannot be proteolytically inactivated – FGF23 stays active longer.
Autosomal Dominant Hypophosphatemic Rickets
ADHR
Recessively inherited hypophosphatemic rickets Due to mutations in Dmp1
• Dmp1 expressed by osteocytes and negatively regulates
FGF23
• Mutation in Dmp1 leads to overproduction of FGF23
Autosomal Recessive
Hypophosphatemic Rickets
Form of hypophosphatemic rickets Due to heterozygous or homozygous loss of function
mutations in type II sodium phosphate cotransporter NaPiIIc. This results in elevated levels of 1,25 (OH)2D3
Hereditary Hypophosphatemic Rickets with Hypercalciuria (HHRH)
Factors secreted into circulation by tumors
cause alterations in Pi metabolism that
mimic hyophosphatemic rickets
Tumor Induced Osteomalacia (TIO)
What are the two forms of Hyperphosphatemia?
Acute/ short term
Chronic
_________ Suppresses 1 α-hydroxylase activity in kidney, lowering
1,25D3 levels, which further exacerbates hypocalcemia by reducing Ca2+ uptake in gut/renal reabsorption
acute (short term) hyperphosphatemia
_______ results in Soft tissue (incl. vasculature) calcification, renal failure, 2ry hyperparathyroidism, renal osteodystrophy.
Chronic hyperphosphatemia
