Parathyroid and regulation of calcium (L8) Flashcards
Important physiologic processes involving calcium (6)
Membrane stability and cell function Hormone secretion Bone structure/formation Blood coagulation Muscle function Neuronal transmission
Important physiologic processes involving phosphate (5)
Cellular energy (ATP) Intracellular signalling pathways Nucleic acid backbone Bone structure Enzyme activation/deactivation
Indicator of free calcium availability
Calcium bound to albumin minus the concentration of albumin
Two primary regulators of calcium concentration
Parathyroid hormone and vitamin D/calcitriol
Daily calcium turnover in humans
1000 mg intake Half absorbed in the intestines Some also excreted Net ~200 mg absorption ~200 mg excreted in urine
Chief cells of parathyroid gland
Synthesize PTH
Oxyphil cells
Unknown function, increase with age
1-84 fragment
Half life of 4 minutes, clinically important for measurement
N-terminal fragment
1-34: biologically active
C-terminal fragment
35-84: has longer half life than others, but is inactive
Parathyroid hormone related peptide
Mimics action of PTH in bone and kidney
Physiologic concentration of PTHrP
Normally very low, doesn’t affect Ca2+ concentrations; however, some tumors secrete it and cause hypercalcemia
Primary parathyroid hormone receptor
PTH1R, present in the osteoblasts and kidneys
Second messengers of PTH1R
Adenylyl cyclase/cAMP pathway
IP3/DAG pathway
To what does the PTH1R bind?
1-34 fragment, 1-84 fragment, PTHrP
PTH2R
Only binds to 1-34 fragment, function is unclear
Net effects of PTH on the bones and kidney
Increases plasma Ca2+ concentration, decreases plasma Pi concentration
How much of the body’s calcium is in the bone?
99%
PTHR expression on bone cells
Present on osteoblasts, but not on osteoclasts
Difference in derivation between osteoclasts and osteoblasts
Osteoblasts: from mesenchymal stem cells
Osteoclasts: from hematopoietic stem cells
Osteocytes
Terminally differentiated from osteoblasts; make up most of the bone matrix
M-CSF
Macrophage colony stimulating factor; stimulates differentiation of osteoclasts
PTH stimulation of osteoclasts
INDIRECT through M-CSF
RANK ligand
Leads to maturation of osteoclasts and bone resorption, stimulated by PTH
Osteoprotegerin
Antagonist of RANKL
Hormonal regulation of OPG
Estrogens stimulate; glucocorticoids inhibit
How does the osteoclast resorb bone?
Releases H+ and acid proteases into the lacuna, dissolving bone mineral and hydrolyzing bone matrix proteins
PTH stimulates what gene in the kidney?
CYP1alpha, which encodes for 1alpha-hydroxylase
1-alpha-hydroxylase
Converts Vitamin D3 into its active form
What does PTH do to the infrastructure in the kidney?
Stimulates insertion of calcium protein channels into the apical membrane of distal tubule
PTH effect on phosphate in the kidney
Reduces phosphate absorption in both proximal and distal tubules; greater in the proximal
Calcium sensing receptor - location
Located in chief cells, kidney tubules, and C cells
What does CaSR do?
Binds ionized calcium, inhibits PTH synthesis at the promoter level, and degrades existing PTH
What does Vitamin D3 do?
Binds VDR, inhibits PTH synthesis at the promoter level, and stimulates CaSR transcription
Calciferol
Refers to vitamin D in all its forms
Cholecalciferol
Directly refers to vitamin D3
Calcidiol
25-hydroxyvitamin D3; immediate precursor
Calcitriol
1,25-dihydroxyvitamin D3 (active form)
Ergocalciferol
Vitamin D2 from vegetables
Synthesis of vitamin D3 in the skin
Precursor hormone 7-dehydrocholesterol is converted to cholecalciferol in the skin by UV light, then isomerized to form vit D3
How is vitamin D transported to the liver?
Either directly through portal circulation or indirectly through chylomicron association
Default pathway for vit D3 conversion
To the inactive form; 24,25-dihydroxyvitamin D3
Factors driving conversion from inactive to active vitamin D3
Hypocalcemia or hypophosphatemia
Direct effects of vitamin D3 on bone
Mobilize calcium from bone
Stimulation of osteoclast proliferation/differentiation
Indirect effect of vitamin D3 on bone
Increases plasma calcium concentration, which promotes bone mineralization
Effects of vitamin D3 on the intestines
Increases calcium absorption from duodenum
Increases phosphate absorption from small intestine
Vitamin D3 and pathway of calcium reabsorption in the gut
Upregulates TRPV5/6 (apical membrane), calbindin (intracellular), and calcium ATPase pump (basolateral)
Vitamin D3 and the pathway of phosphate reabsorption in the gut
Increases Pi-Na cotransporter
Deficiency in vitamin D3 is linked to these conditions (6)
MS Asthma Major depressive disorder Colon/breast cancer CVD DMII
Normal serum calcium range
8.8-10.3mg/dL
Normal serum phosphate range
2.4-4.1mg/dL
Urinary hydroxyproline
Evidence of enhanced bone resorption
Osteoporosis definition
Decreased bone density, mostly in the trabeculae
Causes of osteoporosis
Genetic, menopause (decreased estrogen), prolonged GC therapy/prolonged stress, low dietary calcium
Treatment of osteoporosis
Estrogen replacement, bisphosphonates, calcitonin, vitamin D supplementation
Primary hyperparathyroidism
Hyperplasia or carcinoma of the parathyroid, causing hypercalcemia and kidney stones
Secondary hyperparathyroidism
Usually due to CRF; lack of vitamin D3 causes excess PTH from lack of inhibition
Symptoms of hypoparathyroidism
Hypocalcemic tetany
Chvostek’s sign
Stimulation of facial nerve causes facial muscle twitching
Rickets
Vitamin D deficiency in children that causes “bowing” of long bones and decreased bone strength
Osteomalacia
Vitamin D deficiency in adults that causes decreased bone strength
Calcitonin - location and length
Made in the C cells of the thyroid gland; 32 amino acids long
What is the normal physiologic importance of calcitonin?
Unclear. Pathology/absence of C-cells does not alter calcium concentration
Therapeutic use of calcitonin
Slows bone turnover and inhibits osteoclasts
Paget disease
Localized regions of very high bone resorption rates and reactive sclerosis; cause unknown
Escape phenomenon
Rapid downregulation of calcitonin receptors inhibits antiosteoclastic actions of calcitonin within a few hours; makes it a less effective treatment option