Calcium and Phosphate Regulation Flashcards
What is the normal range of Ca?
Tightly regulated range in plasma (2.2 - 2.6 mM)
What is the most abundant cation?
Calcium
What is the function of phosphate?
Cellular energy metabolism (ATP) Intracellular signaling pathways Nucleic acid backbone Bone structure Enzyme activation/deactivation
What is the function of calcium?
Membrane stability and cell function Neuronal transmission Bone structure/formation Blood coagulation Muscle function Hormone secretion
What is Ca found as in the plasma?
Half Ca is bound to albumin
Half is ionized
What is Pi found as in the plasma?
Most of Pi is ionized
What does hypocalcemia result in?
Muscle failure, tetany, convulsions, death
What does hypercalcemia result in?
Renal dysfunction, calcification of soft tissues, muscle weakness, coma
What often causes hyperphosphatemia?
Result of severe tissue injury “crush”
What are the main 2 regulators of calcium?
PTH
Vitamin D
What is the function of the chief/principal cells in the parathyroid gland?
Make PTH
What is the function of the oxyphil cells in the parathyroid gland?
No known function, increase with age and chronic kidney disease
What is the function of the 1-34 PTH fragment (N terminal)?
N-terminal fragment 1-34 biologically active – binds to PTH receptor
What is the function of the 35-84 PTH fragment?
C-terminal fragment 35-84 has longer half-life than other fragments – inactive
What is the clinical importance of the 1-84 PTH fragment?
Intact 1-84 fragment: half-life of 4 min and is clinically measured.
How is PTH synthesized?
The signal peptide directs it to the ER for processing after translation
What is the function of PTHrP (related peptide)?
Parathyroid hormone-related peptide (PTHrP) is highly homologous to PTH 1-34 AA.
It mimics the action of PTH in the bone and kidney.
What is the relationship of PTHrP to disease?
Many tumors produce PTHrP (renal, bladder, lymphoma, head/neck) resulting in hypercalcemia
What are the PTH receptors?
PTH 1R
PTH 2R
Describe PTH 1R.
Primary receptor and is found in the osteoblasts and kidney and it is a GPCR.
Binds 1-34 fragment, 1-84, PTHrP
Describe PTH 2R.
Physiological importance in humans unclear
Binds 1-34
Does not bind PTHrP
What are the targets of PTH?
Bone and Kidney
What are the effects of PTH?
Increase plasma Ca2+, decrease plasma Pi
What is the function of osteoclasts?
Bone reabsorption
Do not express PTH receptors
What is the function of osteoblasts?
Bone formation and mineralization
High expression of PTH receptors
What is the mechanism of PTH action?
- PTH stimulates macrophage colony-stimulating factor (M-CSF) in osteoblasts by binding the PTH receptor.
- M-CSF stimulates differentiation of osteoclast precursors
What is the the type of action PTH has on osteoclasts?
Indirect via M-CSF from the osteoblasts
What is the effect of PTH on RANK ligand?
PTH stimulates RANK ligand – leads to maturation of osteoclast and bone reabsorption. Bone degradation releases Ca2+ and Pi to systemic circulation.
What is Osteoprotegerin (OPG)?
It is an antagonist of RANK ligand which leads to the down regulation of osteoclasts
How does increased cortisol lead to osteoporosis?
Cortisol inhibits OPG -> more bone breakdown and can lead to osteoporosis
How does PTH affect the kidney?
Stimulates CYP1α – encodes 1alpha-hydroxylase
What is the function of 1alpha-hydroxylase?
Converts Vitamin D into its active form
How does the active form of Vitamin D affect the kidney?
Stimulates Ca2+ channel insertion in apical membrane of distal tubule
What is the main regulator of PTH?
Ca concentration in the plasma
How does the parathyroid gland detect changes in Ca?
CaSR - the calcium sensing receptor
What is the function of the CaSR?
Located in chief cells, kidney tubules, C cells and it binds ionized Ca2+.
It has 2 functions:
• Inhibits PTH synthesis at
promoter level
• Stimulates degradation of preformed PTH
How does Vitamin D regulate PTH?
Binds nuclear receptor - VDR
- Inhibits PTH synthesis at promoter level
- Stimulates CaSR gene transcription – indirect regulation of PTH
What is Calciferol?
General term for vitamin D and other natural structural analogs.
What is Cholecaciferol?
Vitamin D3 from animals
What is Calcidiol?
25-D
What is Calcitriol?
1,25-D (active form)
What binds Vitamin D in the plasma?
Vitamin D- binding protein
What are the targets of Vitamin D?
Bone
Kidney
Intestine
What target of Vitamin D does PTH NOT act upon?
Intestine. PTH acts on the intestine via the effects of Vitamin D.
How does Vitamin D directly affect the bone?
Mobilize Ca2+ from bone
Osteoblasts and osteoclasts have VDRs so Vitamin D stimulates osteoclast proliferation/differentiation.
What is an indirect effect of Vitamin D on the bone?
It increases the plasma Ca so it then causes bone mineralization to occur
How does Vitamin D affect the intestine?
Increases transcellular Ca2+ absorption in duodenum
Stimulates Pi reabsorption from small intestine
What is osteoporosis and what causes it?
Reduced bone density – mainly trabecular bone
Causes: genetic, menopause (low estrogen), glucocorticoid therapy/chronic stress, low dietary Ca2+
What are the causes of hyperparathyroidism?
Hyperplasia, carcinoma of parathyroid gland
What are some of the effects of hyperparathyroidism?
Hypercalcemia, kidney stones and renal failure which leads to reduced Vitamin D -> excess PTH synthesis.
What is the function of bisphosphonates used in treatment of osteoporosis and what is their problem?
Bisphosphonates inhibit osteoclasts so that
bone cannot be broken down and it can cause hairline fractures that will not be fixed by bone cycling
What are some of the effects of hypothyroidism?
Hypocalcemic tetany -> due to increased excitability of neurons
What causes rickets in children and osteomalacia in adults?
Unmineralized bone due to Vitamin D deficiency
What is pseudohypoparathyroidism?
Congenital defect in G protein that associates with PTHR1.
It causes a generalized resistance to PTH, TSH, LH, and FSH which leads to these symptoms:
- low Ca++
- high phosphate
- elevated PTH
- short stature
What is the normal serum Pi level?
0.8-1.45 mM
What is the role of calcitonin in Ca regulation?
Normal physiological importance is unclear
What is the use for calcitonin clinically?
Inhibits osteoclast reabsorption of and slows bone turnover
What is the escape phenomenon associated with calcitonin therapy that can prove problematic?
“Escape” phenomenon – rapid downregulation of calcitonin receptors cause the antiosteoclastic actions of calcitonin to diminish within a few hours making this a less effective treatment option.
