L75: Parathyroid and Regulation of Calcium Flashcards
What is a good indicator of free calcium availability?
Albumin levels: calcium bound to albumin
What are the 2 primary regulators of Calcium?
Parathyroid Hormone
Vitamin D/Calcitriol
Which organs govern calcium homeostasis?
Intestines, Kidney, Bone
Where is the parathyroid gland?
On anterior surface of thyroid gland
What cells are found in the parathyroid gland and what do they do?
Chief Cells: produce PTH
Oxyphil Cells: unknown, increases with age
How is PTH synthesized?
Signal peptide on preproPTH directs peptide to ER -> Processed to Pro-PTH sequence after signal peptide cleaved -> vesicles -> PTH secreted as 84 residue molecule (Active sequence: 1-34, C term fragment: 35-84)
Which part of the secrete PTH binds to the PTH receptor?
N terminal fragment 1-34 is the biologically active component
What is unique about the C terminal fragment 35-84 from PTH?
Longer half life than biologically active part of PTH and inactive
What is PTHrP
PTH related peptide: mimics PTH actions in bone and kdney
is NOT a regulator of plasma Calcium
What usually produces PTHrP?
Tumors-> leads to hypercalcemia
What is the primary PTH receptor?
PTH 1R: found in osteoblasts and kidney
What kind of receptor is PTH 1R and what does it bind?
GPCR: Gas-> AC/cAMP pathway; Gaq->PLC/IP3/DAG
Binds: 1-34 fragment, 1-84, and PTHrP
What is PTH 2R?
Another PTH receptor that binds the 1-34 fragment of PTH
Does NOT bind PTHrP
Unclear of importance in humans
What are the targets of PTH and their net effects?
Targets: Bone and Kidney
Net EffectS: Increase plasma Calcium and decrease plasma phosphate
Where is the vast majority of calcium present in?
99% found in bone
What do osteoblasts do?
Bone formation and mineralization
High expression of PTH receptors
Where are osteoblasts derived from?
Mesenchymal Stem Cells
What do osteoclasts do?
Bone reabsorption
Do NOT express PTH receptors
Where are osteoclasts derived from?
hematopoietic stem cells
What are osteocytes?
Make up most of bone matrix
Where do osteocytes derive from?
Terminally differentiated osteoblasts
How does PTH affect bone remodleing?
PTH stimulates M-CSF in osteoblasts-> M-CSF stimulates differentiation of osteoclast precursors -> PTH stimulates RANK-ligand -> osteoclasts mature-> bone reabsorption -> bone degradation leads to release of calcium and phosphate into blood
What is osteoprotegerin (OPG)?
Antagonist to RANK ligand ->prevents association with RANK on osteoclast precursors-> prevents maturation of osteoclasts
What regulates OPG?
Estrogens stimulate OPG
Glucocorticoids inhibit OPG
How do osteoclasts reabsorb bone?
Secrete H+ and acid proteases into lacuna -> dissolves bone mineral and hydrolyze bone matrix proteins
What does the PTH do in the kidney?
Stimulate CYP1a(1a-hydroxylase) -> converts to active form of Vitamin D3
Stimulate Calcium channel insertion on the apical membrane of distal tubule
REduce phosphate reabsorption
Where in the kidney does PTH exert its effects?
Thick Ascending limb
Distal tubule
Proximal tubule
What is CaSR?
Calcium sensing receptor
Binds ionized Calcium -> regulates PTH by inhibiting its synthesis at the promoter level
Also stimulates degradation of preformed PTH
Where are CaSRs found?
Chief Cells, Kidney Tubules, C cells
What role does Vitamin D play in PTH regulation?
Binds nuclear receptor (VDR) to inhibit PTH synthesis at promoter level
Stimulates CaSR gene transcription -> indirect regulation of PTH
How does PTH stimulate Osteoclasts?
Indirectly through M-CSF secretion stimulation in osteoblasts
What is calciferol?
General term for Vitamin D and natural sturctural analogs
What is cholecalciferol?
Vitamin D3 (animal tissues)
What is calcidiol?
25-hydroxy-vitamin D (25-D): immediate precursor to active Vitamin D
What is Calcitriol?
1,25-dihydroxy-vitamin D (1,25-D): active form of Vitamin D
What is ergocaliferol?
Vitamin D2 from vegetables
Where is Vitamin D3 derived from?
From cholesterol (steroid hormone)
What receptor does Vitamin D3 bind?
Nuclear receptor VDR
How is Vitamin D3 transported?
Bound to vitamin D binding protein
How is Vitamin D3 synthesized in the skin?
Precursor hormone (7-dehydr/ocholesterol) converted to cholecalciferol in skin by UV -> isomerized -> Vitman D3 -> binds to Vitamin D binding protein in circulation -> transport to liver
How do you activate vitamin D3 and vitamin D2 from the diet?
1a-hydroxylase enzyme in kdiney via stimulation from PTH
How is Vitamin D3 metabolized?
VitD3 transported from skin to liver
VitD3 and D2 from diet are transported to liver directly via portal circulation or indirectly via chylomicrons
LIVER: hydroxylated to calcidiol (25- D) -> goes to kidney to convert to active Calcitriol (1,25-D) by 1a-hydroxylase
What is the default pathway for Vitamin D3 synthesis?
Inactive form 24,25-D
What is the sequence in the pathway for active vitamin D3 synthesis?
7-dehydrocholesterol(skin) -> UV light -> Cholecalciferol-> liver -> Calcidiol(25-D3) -> Kidney(1a Hydroxylase) -> Calcitriol (1,25D3) active form
What conditions lead to the active form pathway for Vitamin D?
Key Factors: hypocalcemia and hypophosphatemia
Others: Vitamin D deficiency, Increased PTH
What are the effects of Vitamin D on bone?
Direct:
mobilize calcium from bone via VDRs on osteoblasts and osteoclasts
stimulate osteoclast proliferation/differentiation
Indirect:
Increase plasma calcium to promote bone mineralization
What are the effects of Vitamin D on the intestine?
Increase transcellular Calcium absorption in duodenum by increasing expression of TRPV5/6
Stimulate phosphate reabsorption from small intestine
How does Vitamin D promote calcium reabsorption transcellularly in the intestine?
Vitamin D-> inc TRPV5/6 -> Calcium comes in from luminal side -> binds to Calbindin -> goes through membrane calcium ATPase pump on other side
How does Vitamin D promote phosphate absorption in the intestine?
Vitamin D -> inc expression of Na+/Pi cotransporter -> secrete 2 Na+ for 1 phosphate
Does Vitamin D show pleiotropic effects?
Yes
What can Vitamin D deficiency lead to?
MS Asthma CV disease DM T2 Colorectal/breast cancer Depressive disorder
How does vitamin D affect immune cells?
induces differentiation
How is low blood calcium regulatd?
Hypocalcemia -> inc PTH =>
inc CYP1a-> inc 1,25D (calcitriol -> inc dietary calcium absorption in intestine, inc bone turnover-> inc blood Ca
inc bone turnover +inc Ca2+ reabsorption and inc phosphate excretion in kidneys -> inc blood Ca2+
How are low serum calcium and high serum phosphate dealt with?
PTH infusion normalizes them
What is the normal range for serum calcium? phosphate?
Calcium: 2.2-2.6 mM
Phosphate: 0.8-1.45 mM
What is osteoporosis? What cases it?
Reduced bone density in trabecular bone
Causes: Genetics, Menopause(low estrogen), Glucocorticoid/stress, low dietary Caclium
How do you treat osteoporosis?
Estrogen
Calcitonin
Bisphosphonates
Vitamin D
What are the 2 forms of hyperparathyroidism?
Primary: hyperplasia, carcinoma of Parathyroid gland->leads to hypercalcemia and kidney stones
Secondary: due to chronic renal failure -> reduced Vitamin D -> excess PTH secretion
What is seen with hypoparathryoidism?
hypocalcemic tetany (low calcium levels lower the threshold for depolarizaiton)
Chvostek Sign
What is Chvostek Sign?
twitching of facial muscles in response to tapping facial nerve
What causes rickets(children)/osteomalacia (adults)?
Unmineralized bone due to Vitamin D deficiency leading to decreased bone strength
What is calcitonin?
Peptide produced in C cells of thyroid gland with unclear importance in normal physiology
What happens to calcium levels with thyroidectomy but intact parathyroid glands??
No change in normal range of calcium (calcitonin thus is not a major regulator of calcium)
What happens to calcium levels with C cell tumors?
Tumors -> very high levels of calcitonin -> but no changes seen in calcium levels => calcitnon is not a major regulator of calcium
What uses does calcitonin have?
Therapeutic: inhibit osteoclast reabsorption of bone and slows bone turnover- > leads to hypocalcemic effect
What is Paget disease and how can it be treated?
Excessive localized regions of bone resorption and reactive sclerosis leading to very high bone turnover
Treat with calcitonin
What is the escape phenomenon in relation to calcitonin
Rapid downregulation of calcitonin receptors -> leads to diminished anti-osteoclastic effects of calcitonin -> makes it become less effective treatment option
