1
Q
1,25 Dihydroxycholecalciferol
1,25 DHCC or 1,25[OH]2D3
A
- steroid hormone derived from vitamin D
- increases Ca2+ absorption from intestine
2
Q
parathyroid hormone (PTH)
A
- secreted by the parathyroid gland
- mobilizes Ca2+ from bone
- increases phosphate excretion
- biological activity is dictated mainly by N-terminal half of the molecule
3
Q
calcitonin (CT)
A
- hormone secreted by cells in thyroid gland
- calcium lowering
- inhibits bone resorption
4
Q
roles of calcium
A
secondary messenger excitation/contraction coupling fertilization visual excitation *neuromuscular excitability (open or close ion channels)
5
Q
hypocalcemia
A
- hypocalcemic tetany: inc excitability of nerve and muscle cells (spams)
- neg effects on blood clotting
6
Q
hypercalcemia
A
cardiac arrhythmia
depressed neuromuscular excitability
7
Q
Ca2+ balance
A
loss = gain
- amount absorbed by gut decreases as one gets older
- abs > excretion: excess to bones
- exc > abs: deficit from bones
8
Q
Ca in bones
A
- 20% in rapidly exchangeable pool. homeostasis with plasma Ca2+.
- remainder in stable pool. homeostasis with bone remodeling - constant resorption and deposition.
- small changes in rate of resorption or deposition have large impact on Ca2+ metabolism.
9
Q
Ca in kidney
A
large amount is filtered
98% resorbed
regulated by hormones
10
Q
Ca in GI tract
A
actively transported by Ca-dependent ATPase
-regulated by 1,25[OH]2D3, through negative feedback
11
Q
bone structure
A
- collagenous matrix with calcium phosphates (hydroxyapatite)
- cellular and well vascularized
- outer layer of compact bone (denser, less metabolically active)
- inner layer of trabecular (spongy) bone
12
Q
bone cells
A
- osteoblasts: secrete collagen, form a matrix that calcifies. from fibroblast-like precursor
- osteocytes: differentiated osteoblasts surrounded by bone matrix. branching processes through bone.
- osteoclasts: multinuclear cells that digest and resorb bone. monocyte derived. secrete acids and proteases.
13
Q
endosteum
A
layer of cells that separates bone marrow space from bone
14
Q
periosteum
A
layer of cells that cover outer surface of bone
15
Q
bone mineralization
A
balance between calcium and phosphate
-osteoblasts secrete alkaline phosphatase that cleaves pyrophosphate, increasing phosphate to promote calcium phosphate crystallization
16
Q
vitamin D + D3 (formation, transport)
A
- group of related sterols
- produced by action of sunlight on pro-vitamins
- D3 can be prod. in body by UV light on 7-dehydrocholesterol in skin
1. transported from skin by vitD- binding protein in plasma
2. D3 hydroxylated in liver, returned to blood (bound to D3BP)
3. in renal tubules 25OHD3 further hydroxylated to form biologically active form 1,25(OH)2D3 - lower affinity for D3BP, shorter half life
17
Q
1,25(OH)2D3 production in kidney
A
stimulated by PTH, hypocalcemia, hypophosphatemia
-PTH through enhancing phosphate diuresis, decreases intracellular phosphorus conc. in kidney, increasing prod. of 1,25(OH)2D3
*hypophosphatemia stimulates kidney to produce 1,25(OH)2D3
[hyperphosphatemia is potent inhibitor of 1,25(OH)2D3 prod]
18
Q
action of 1,25(OH)2D3
A
-provide Ca2+ and phosphate to ECF for bone mineralization
19
Q
vitamin D deficiency
A
children: rickets
adults: osteomalacia
- reduced bone mineralization (but D3 doesn’t promote Ca deposition in bone)
20
Q
vitamin D receptor (VDR)
A
- 1,25(OH)2D3 acts by binding to nuclear VDR
- VDR is transcription factor, codes for calcium-binding proteins (CaBP), and calcium and phosphate transporters
- VDR in Ca2+ reg tissues (intestine, bone, kidneY0 and others (PTH, pancreas, skin, etc.)
21
Q
recommended vit D3 intake
A
birth-50 yo: 200IU/day
50-70 yo: 400 IU/day
>70 yo: 600 IU/day
higher levels recommended for protection against colorectal and other cancers
22
Q
1,25(OH)2D3 action + uptake: GI (4)
A
- increase Ca pumping out of basolateral membranes in intestines
- promotes phos + Ca uptake (inc plasma levels)
- Ca entry enhanced by 1,25(OH)2D3-induced increases in epithelial calcium channels (ECaC) + intracellular Ca binding protein (calbindin) in mucosal cells
- inc Ca entering cells excreted at serosal side with Ca pumps and Ca/Na exchange (also upreg by 1,25(OH)2D3)
23
Q
1,25(OH)2D3 action: bones (1)
A
- mobilizes Ca and phos. by inc pumping through osteoblasts
- works synergistically with PTH, alone far less effective in mobilization
24
Q
1,25(OH)2D3 action: kidney (3)
A
- facilitates Ca and phos. reabsorption, permissive role in supporting PTH action
- proximal nephron: inc expression of one form of Na-dependent phosphate transporter
- distal nephron: induces formation of ECaC and calbinin in cells
25
1,25(OH)2D3 regulation
plasma Ca + phos reg. 1,25(OH)2D3 by negative feedback of 1a-hydroxylase. synthesis of 1a hydroxylase stim by inc PTH and low phos.
- neg feedback through plasma Ca2+ and phos.
- neg feedback through 1,25(OH)2D3 overproudction on 1a-hydroxylation
- pos feedback through 1,25(OH)2D3 stimulation of renal 24-hydroxylase and production of 24,25(OH)2D3 (possible degradative pathway)
26
parathyroid gland (anatomy)
- four glands (2 inferior, 2 superior)
- embedded in thyroid, near pharynx
- chief cells: make PTH
- oxyphil cells: unkown function
27
PTH synthesis
1. pre-pro-hormone
2. cleavage to pro-hormone
3. cleavage to mature hormone
- PTH is cleaved and stored in chief cells, secreted with stimulation
- half live 20 min, then rapidly cleared in liver (Kupfer cells) into 2 polypeptides
28
calcium sensor
- PTH glands monitor blood's ionized Ca 2+ levels with 7TM rec, "Ca sensor"
- when ionized Ca decreases, sensor in chief cells immediately recognizes
- signal transduction, inc PTH sec
- when ionized Ca inc, Ca sensor no longer stimulated, dec sec of PTH
29
actions of PTH (5)
PTH acts via receptor activation of -proteins, production of cAMP and IP3
1. inc. bone resorption + mobilizes Ca by inc permeability of Ca in bone fluid of osteoclasts + osteoblasts: pump Ca2+ into ECF
2. dec plasma phos. and inc urine phos. excretion (phosphaturic action)
3. inc Ca reabsorption in distal tubules
4. inc formation of 1,25(OH)2D3 (stim 1a-hydroxylase), inc Ca absorption in intestine (no direct effect)
5. inc formation of osteoclasts + osteoblasts (but bone resorption dominates)
30
PTH + VD3 on bone
each interact with their receptor on mature osteoblasts
| -either stim activation of receptor activator of nuclear factor kB ligand (RANKL) on surface of osteoblast
31
RANKL + RANK interaction
precursor monocytic osteoclasts have receptor for RANKL, receptor activator of nuclear receptor kB (RANK)
- RANK on preosteoclast surface interacts with osteoblast's RANKL
- signal transduction to induce preosteoclast to mature to multinulcleated giant osteocalst
32
mature osteoclast action
secretes hydrolytic enzymes and HCl, dissolving mineral and matrix of bone, releasing Ca2+ into ECF
-signaled from cytokines from osteoblasts and extracellular environment
33
osteoprotegerin (OPG)
soluble ligand, bind to and block RANKL
- keeps RANKL from interacting with + activating RANK
- body's regulation of number of preosteoclasts that can interact with osteoblast's RANK
- regulators (i.e. estrogens) enhance OPG production, depressing RANKL (and bone resorption)
- regulators (i.e. cortisol) inhibit OPG production (promoting bone resorption)
34
PTH on kidney (3)
- increases Ca reabsorption in distal nephron (low capacity, high PTH can inc plasma Ca such that filtered load exceed reabsorption threshold, inc urine Ca)
- inhibits reabsorption of phosphate in proximal tubule
- promotes hydroxylation of 25OH-D3
35
phosphaturic action (PTH + kidney, 2)
1. phosphate reabsorption in proximal nephron is inhibited by PTH
- PTH activates adenyl cyclase in basolateral membrane, inc cAMP
- cAMP inactivates Na/(PO4)3- cotransporter in luminal membrane
2. PTH inc conversion of 25OHD3 to active 1,25(OH)2D3, inc Ca uptake in SI
36
FGF-23 (phosphaturic action)
(family of fibroblast growth factors, regulator of phosphate)
-high FGF-23 dec Na/(PO4)3- cotransporters in luminal membrane, reducing phosphate reabsorption from tubular fluid (inc. loss in urine)
-also decrease hydroxylation to active 1,25(OH)2D3, promotes formation of inactive 24,25(OH)2D3, which decrease phosphate uptake in SI
[overall dec plasma phosphate]
37
FGF-23 levels
-inc with inc dietary phosphate intake
-dec on dec dietary phosphate intake
-produced by osteoblasts in response to inc 1,25(OH)2D3
[creates feedback control loop for 1,25(OH)2D3 production in kidney via FGF-23 regulation
38
PTH + Magnesium
| low + high levels
- can influence serum Ca levels
- with Mg deficiency, bone resorption (PTH response) is inhibited, results in decrease of Ca released into blood. PTH secretion and synthesis can be impaired.
- high Mg can inh PTH production
39
Mg + enzymes
- important activator, enz that hydrolyze and transfer phosphate groups
- CVS: ATP metabolism, Na/K ATPase
- Mg deficient, enz. activity of Na/K ATPase impaired. have inc K+ to ECF and inc Na+ to ICF, alters membrane potential
40
body store v. serum Mg
- serum Mg levels often fail to accurately reflect body's stores
- may be depleted with normal serum Mg
41
Mg intake processing
- 1/3 of daily intake absorbed in ileum, excreted in urine
| - 50-60% Mg filtered by kidney reabsorbed in LoH. LoH diuretics can inc Mg in urine.
42
PTH secretion regulation (3)
1. Ca levels act directly of PT gland.
- inc Ca inh PTH sec + Ca deposited in bone.
- dec Ca, inc PTH secretion, Ca mobilized from bone
2. 1,25(OH)2D3 acts directly on PT gland to dec production of pre-pro PTH
3. chronic kidney disease, dec formation of 1,25(OH)2D3, so low plasma Ca, overstim of PT gland, secondary hyperparathyroidism
43
parathyroidectomy
PTH essential
- dec plasma Ca inc neuromuscular excitability, leads to tetany
- PT gland can accidentally be removed with thyroid gland
- results in inc plasma phos.
- injection PTH can correct chemical abnormalities
- Ca injections for temp relief
44
PTH excess (5)
tumor of PT gland, hyperparathyroidism
- hypercalcemia -> cardiac arrhythmia
- hypophosphatemia (phos excreted in excess, low plasma phos.)
- demineralization of bones (due to inc resorption)
- hypercalciuria (amount filtered greater than can be reabsorbed)
- Ca containing stones
45
PTH-related peptide (PTHrP)
- found in plasma of patients with certain malignancies
- leads to hypercalcemia -> dec serum PTH
- all physiological actions of PTH (inc bone resorption, inc renal Ca2+ reabsorption, dec phos reabsorption)
46
calcitonin
- secreted by parafollicular cells of thyroid gland (C-cells)
- also in CSH, brain, lungs, GI (thyroidectomy doesn't lead to no calcitonin)
47
stim/inh of calcitonin secretion
-sec when thyroid gland perfused with high Ca (similar Ca sensor as PT gland)
high Ca binding inc calcitonin sec. (PTH binding to thyroid inh CT sec)
-not sec when Ca < 9.5mg/dL
-if Ca > 9.5, CT concentration is proportional to plasma Ca levels
-half life: 10 min
48
actions of calcitonin (7)
1. dec plasma Ca and phos, dec bone resorption. acts via calcitonin rec on osteoclasts,, inh resorption, dec Ca perm in osteoclasts and osteoblasts.
2. inc Ca excretion urine
3. after thyroidectomy, Ca and bone density normal if PTH sec is normal, CT from other tissues play role
4. hypersecretion CT - no symptoms
5. may have more active role in children during skeletal formation
6. may protect against post-prandial Ca inc
7. in pregnancy + lactation: 1,25(OH)2D3 levels inc, would lead to bone loss if CT didnt also inc
49
Ca2+ level: glucocorticoids
- excessive GCs, negative Ca balance
- dec absorption of Ca by intestine, inc excretion by kidney
- initial hypocalcemia corrected by in PTH w/ bone resorption
- since GCs inhibit osteoblast formation, balance shifted toward bone resorption (osteoporosis)
50
Ca2+ level: GH
-GH increases Ca level by increasing intestinal absorption
51
Ca2+ level: T3 + T4
-THs inc Ca by inc bone resorption
52
Ca2+ level: estrogens
- estrogens dec osteoporosis by counteracting effect of PTH on bone and promoting effect on kidneys (Ca reab, inc phos excretion)
- severity of osteoporosis after menopause dep on max bone density at age 25, calcium intake, exercise
53
Ca2+ level: insulin
insulin increases bone formation
54
Ca2+ level: bone metastasis
erosion of bone
| hypercalcemia
55
osteoblasts
- sec alkaline phosphatase to leave pyrophosphate during mineralization. reduces stabilization + inc phosphate to promote calcium crystallization
- also lay down collagen and other proteins to form bone matrix for mineralization
- derive from fibroblast-like precursors
56
osteoclasts
- carry out bone resorption
- large multinucleated cells derived from monocytic precursors
- secrete acids and proteases that dissolve mineral crystals and protein matrix from bone
57
Action of 1,25(OH)2D3
| [3 roles]
1. inc calcium and phosphorus uptake from SI
2. inc bone permeability
3. inc calcium and phosphorus reabsorption in kidney
58
Action of PTH
| [3 roles]
1. inc bone resorption
2. inc calcium reabsorption from kidney
3. inhibits phosphate reabsorption from kidney (phosphaturia)
59
Action of Calcitonin
| [3 roles]
1. has rec on osteoclasts, inhibits bone rebsoption
2. decreases calcium reabsorption from kidney, increases amount excreted in urine
3. levels increase in pregnancy to protect bones, have higher levels of D3
