Endocrine 8: Calcium and Phosphate; PTH Flashcards
List functions of calcium
- most abundant cation (because it is in bone)
- tightly regulated
- membrane stability
- neuronal transmission
- bone formation
- blood coagulation
- muscle function
- hormone secretion
List functions of phosphates.
- energy metabolism
- intracellular signalling pathway
- nucleic acid backbone
- bone structure
- enzyme activation/deactivation
What can hypocalcemia lead to?
- muscle failure
- tetany
- convulsions
- death
What can hypercalcemia lead to?
- renal dysfunction
- calcification of soft tissue
- muscle weakness
- coma
What can lead to hyperphosphatemia?
crush injury
- severe tissue injury leaks phosphate
How is calcium transported in the blood?
- free
- albumin (since 50:50 ratio, measuring albumin is a good indicator of calcium)
- few complexed (phosphates, citrates)
How is phosphate transported in the blood?
- mostly free
- some protein
What are the primary regulators of calcium?
- PTH
- vitamin D (calcitriol)
Define rapidly exchangeable pool.
- constant bone remodeling utilizes calcium storage
- main storage in bones, gut, and kidney
List the primarily cells in the PTH.
- chief cells - make PTH
- oxyphil cells - increase with age and kidney decline
Where is the parathyroid gland located?
on the back of the thyroid
- 4 lobes
- small
Describe the structure of PTH.
- total 1-84 AA secreted
- peptide hormone (prepro => pro => hormone)
- 1-34 AA is biologically active, binds to PTH1R
- 35-84 fragment is not active, but has long half-life
Define PTHrP.
PTH-related-peptide
- highly analagous to 1-34AA
- mimics PTH in bone and kidney
- many tumors produce this => hypercalcemia
- paracrine effect
- binds with equal affinity to PTH1R
Differentiate PTH1R and PTH2R.
PTH1R can bind with equal affinity to PTH and PTHrP - primary receptor - found on osteoclasts and kidney - GPCR - binds 1-34, 1-84, and PTHrP PTH2R can bind only to PTH
What is the net effect of PTH?
- increase plasma Ca (via bone resorption)
- decrease plasma Pi
Define osteoblasts.
- support bone mineralization and bone formation
- PTH target (high expression of PTH1R)
- derived from mesenchymal stem cells
Define osteoclasts.
- bone breakdown/resorption
- derived from HSCs
- do NOT express PTH1R
Define osteocytes.
- terminally differentiated osteoblasts
- found in bone matrix
What does PTH do in the bone?
- PTH binds to PTH receptors on osteoblasts
- stimulates macrophage-colony stimulating factor (M-CSF) from osteoblasts
- M-CSF stimulates osteoclast differentiation
- stimulates osteoblast expression of RANK-Ligand
- RANKL stimulates RANK expression on osteoclast
- further osteoclast differentiation and bone resorption => release of Ca and Pi from bone into plasma
- osteoblasts take released Ca and Pi and use it to make new bone mineralization
Define OPG.
OsteoProteGerin
- soluble decoy
- antagonist to RANKL
- prevents differentiation of osteoclasts
- no bone resorption, maintains bone
What regulates OPG?
- estrogen stimulates OPG => prevent bone resorption; protective in pre-menopausal women
- cortisol inhibits OPG => allow RANK activation => bone resorption
What does PTH do in the kidney?
- transcription of CYP1a gene
- encodes CYP1a/1a-hydroxylase enzyme
- required for activation of Vitamin D (converts to 1,25-OH-cholecaciferol)
- allows for calcium channel insertion on apical membranes of distal tubule (increase calcium reabsorption)
What is the primary regulator of PTH?
- plasma calcium levels monitored by CaSr on parathyroid gland chief cells, kidney, and thyroid calcitonin C cells
- high calcium = low PTH
- low calcium = high PTH
Define CaSR.
Calcium Sensing-Receptor
- found on chief cells, kidney, C cells
- binds free Ca in the blood
- downstream signaling cascade inhibits PTH gene transcription and promotes degradation of preformed PTH
How does Vitamin D regulate PTH?
- inhibits PTH gene transcription
- promotes transcription of CaSR
- increases PTH sensitivity to Ca (even if little Ca in the blood…will think there is enough..no PTH)
Define calciferol.
any Vitamin D analog
Define cholecalciferol.
Vitamin D3 from animal tissues.
Define ergocalciferol.
Vitamin D2 from plant tissues
Define calcidiol.
25-OH-Vitamin D (25-OH-cholecalciferol)
- immediate precursor to active Vitamin D
- default inactive pathway
Define calcitriol.
1, 25 -OH-cholecalciferol
- active form
- activated by CYP1a or 1a-hydroxylase in the kidney
How is active vitamin D synthesized?
- endogenous cholesterol derivative is activated to vitamin D3 via UV light
- transported to liver via vitamin-D binding protein or chylomicron in blood
- liver converts it to the immediate inactive precursor (25-OH-D)
- transported in peripheral blood attached to DBP
- activated in the kidney via 1a-hydroxylase to 1,25-OH-D
What regulates vitamin D activation?
- calcium levels (low calcium => PTH increase => bone resorption => increase plasma calcium)
- phosphate levels
- low Vitamin D
What are targets of Vitamin D?
bone
kidney
gut
Describe Vitamin D effects in bone.
- mobilize Ca from bone
- stimulate osteoclast differentiation directly via nuclear receptors
- indirect: by increasing calcium absorption and reabsorption in the kidney => increase plasma calcium => promote bone mineralization
Describe Vitamin D effects in gut.
- increase transcellular calcium absorption by promoting transcription of TRPV5/6 and PMCA transport proteins
What happens in hypocalcemic situations?
- low Ca stimulates PTH release
- PTH
===> activates CYP1a in kidney ==> Vit. D activation ==> bone resorption, dietary absorption
===> bone resorption ===> increase plasma Ca
===> reabsorption at the kidney ===> increase plasma Ca - negative feedback
===> vitamin D blocks PTH release
===> increased blood Ca blocks PTH and CYP1a
Define osteoporosis
Causes
- genetic
- menopause (loss of estrogen => loss of OPG => continuous RANK stimulation => continuous resorption)
- stress/glucocorticoids (cortisol increases bone resorption)
- low dietary Ca
Sx: reduced bone density
Tx: estrogen, calcitonin, dietary Ca, bisphosphonates (inhibit bone resorption but can lead to fractures), Vitamin D
Define hyperparathyroidism.
Primary Causes = hyperplasia, carcinoma at parathyroid
- Sx: kidney stones, hypercalcemia
Secondary Causes = chronic renal failure
- reduced vitamin D production => constant PTH release
Define pseudohyperparathyroidism.
- congenital defect in PTH1R G-protein
- also leads to generalized resistance to PTH, LH, FSH, TSH (same G protein)
- Sx: low calcium, high phosphate, high PTH, short stature
Define hypoparathyroidism.
Sx: tetany, low Ca, Chvostek sign of twitching facial nerve
Define rickets/osteomalacia.
rickets = bow legged, children; osteomalacia = adults
- Vitamin D deficiency => unmineralized bone (soft)
- decreased bone strength
Define source and effects of calcitonin.
- thyroid C cells
- inhibits bone resorption
- hypocalcemia actions
