Thirteen/Fourteen Flashcards
(37 cards)
Why is ionized calcium important? What are calcium’s major storage sites? What are the three forms of calcium in circulation? What percent do they each make up? What is a normal range for serum total calcium? Explain which organs allow homeostasis of calcium to be maintained.
- Ionized calcium important for structural support, muscle contraction, clotting, impulse conduction in heart and nerves, intracellular signaling cascades, and exocrine and endocrine secretion events.
- Major storage sites: teeth and bone.
- Three forms in circulation: ionized (50%), protein-bound (40%), soluble complexes (10%).
- Normal range of serum total calcium: 8.5% -10.3 mg/dl.
Calcium homeostasis is maintained by transfer between blood and three major tissues: Bone, kidney, and intestine.
What are the two types of bone mass? What are they like? Where are they located? What percent of mass and area of bone do they make up? What is the BMU? What are its parts?
Cortical: 80% of bone mass, highly
mineralized, appendicular skeleton (arms
and legs)
Trabecular: marrow-containing (spine, metaphyses), comprises 80% of bone surface area, major site of remodeling.
BMU: basic multicellular unit is responsible for bone remodeling.
Osteoclast, osteoblast, osteocyte
Describe the formation, activation, action, and mechanism of action of the osteoclast.
- Role of the osteoclast: derived from precursor monocyte/macrophages. M-CSF (macrophage
colony stimulating factor) directs monocytes to preosteoclast phenotype. Presence of RANK
(receptor for activation of nuclear factor kappa b) which binds to RANKL (RANK receptor
ligand) drives differentiation to the activated state. This can be blocked by OPG
(oseoprotegerin) . Activation of c-Src
(a proto-oncogene product involved
in cell growth control) allows cell to
polarize, attach to the bone (via
integrins) and form a ruffled surface
adjacent to the bone. Proton pumps in
the ruffled membrane secrete H+ ions
which dissolve the hydroxyapatite
crystals in bone and enzymes released
from the osteoclast (cathepsin K and
matrix metalloproteinase 9) cleave the
structural proteins. After about 2
weeks the osteoclasts release from bone and undergo apoptosis.
Describe the formation, activation, action, and mechanism of action of the osteoblast.
- Role of osteoblast:
mesenchymal precursors
(of myocytes, adipocytes, fibroblasts or osteoblasts)
exposed to BMP (bone
morphogenic protein) and
Cbfa1(core-binding factor 1) differentiate into osteoblasts. Further exposure to Cbfa1 activates the osteoblasts.
Osteoblasts follow the furrow left behind by the osteoclasts and deposit osteoid (bone matrix
proteins, mainly type 1 collagen) and minerals forming hydroxyapatite crystals
[Ca10(PO4)6(OH)2]. Osteoblasts last about three months, some go into apoptosis, others transform into osteocytes (90% of cell mass of bone, connected via cytoplasmic processes in the bony cannuliculi).
What is the role of osteocytes?
- Role of osteocytes; thought to be mechanosensors. Increased strain favors bone formation, decreased strain favors bone resorption.
How much calcium is excreted in urine daily? What percent of filtered load is reabsorbed? What percent is reabsorbed in the various parts of the nephron and how?
- Average daily urinary excretion 100-200 mg.
- 80-90% of filtered load reabsorbed.
60-70% in proximal tubule (passive absorption driven by lumen-positive transepithelial potential difference, Ca++/H+ exchanger requires HCO3
no Ca++ transport in descending limb of Loop of Henle
20% in thick ascending limb of Loop of Henle (passive as well, lumen positive transepithelial gradient)
5-10% in distal tubule (where majority of active reabsorption occurs, transepithelial voltage gradient now lumen negative)
remainder in collecting ducts (passive)
Describe the mechanism of action of calcium transport in the distal tubule.
- Distal tubule mechanism: Luminal epithelial calcium channels (ECaC1 and ECaC2, a.k.a. TRPV5 and TRPV6) permit Ca++ entry down the potential gradient
(inside cell negative relative to lumen). Inside cell Ca++ binds to calbindin-D28K and calbindin-D9K (protects against toxic levels and maintains the electrochemical
gradient) which facilitate diffusion to the basolateral membrane, where the plasma membrane calcium
ATPase (PMCA) pumps Ca++ out of cell. There is also a basolateral membrane Na+/Ca++ exchanger (stimulated by PTH). (Fig 14-4,
Kovacs and Ojeda, p. 386)
How does renal filtration affect calcium handling? PTH? How Acidosis? How? Alkalosis? How? Excess dietary salt? How? Loop diuretics? How? Thiazides? How? Vitamin D? How?
- Factors affecting renal Ca++ handling:
Renal filtration: decreases result in decreased urinary Ca++. Increases result in increased Ca++ lost in urine.
PTH improves renal Ca++ reabsorption (see below)
Acidosis or increased dietary acid load impairs reabsorption (increased luminal H+ inhibits TRPV5 Ca++ channels in Distal Tubule)
Alkalosis increases reabsorption (need luminal HCO3 for Ca++/H+ exchange in proximal tubule)
Excess dietary salt decreases reabsorption (solvent drag).
Loop diuretics (e.g. furosemide) decrease reabsorption by decreasing transepithelial voltage gradient in thick ascending limb (inhibition of the Na+/Cl-triporter)
Thiazide diuretics and lithium enhance reabsorption. (Thiazide diuretics work by blocking distal nephron Na+/ Cl co-transporter lowering intracellular Cl-hyperpolarizing the cell. This hyperpolarization opens voltage sensitive
calcium channels [TRPV5] and calcium enters cell.)
Vitamin D (Calcitriol) increases calbindin expression (facilitates transcellular calcium movement).
PTH increases activity of basolateral Na+/Ca++ exchanger further hyperpolarizing the cell and opening TRPV5 channels.
Where does most absorption occur in the intestine? When does active absorption occur? How? When does passive absorption occur? What substances impair absorption? Enhance it?
- Rate of absorption greatest in duodenum, but
long transit time in jejunum means most
absorption there. Of the approximately 1000
mg ingested per day, 360 mg is absorbed (in
equilibrium states that is matched by urinary
and fecal loss of equal amounts of Ca++).
- Absorption is active (across the cell) most
important at low dietary intakes.
- Passive absorption (between cells) important
at high dietary intakes.
- Dietary fiber and phosphate impair absorption.
- Sugars can enhance absorption acutely (e.g. calcium gluconate oral solution).
- Absorption similar to distal tubule, but no calbindin-D28K only calbindin-D9K.
How are PTH levels physiologically controlled? What is the PTH receptor like? What are the 2 basic actions of PTH? What are 4 ways in which it accomplishes those? What are 3 regulators of PTH levels? What are their mechanisms?
- Physiologic control exerted not on secretion, but on production.
- PTH receptor is a G-protein couple receptor signaling through Gs (cAMP and PKA) and through Gq (PLC, PKC and intracellular Ca++ mobilization).
- PTH actions (raise serum Ca++, lower serum PO4)
Stimulates osteoclast reabsorption of bone
Increase renal Ca++ reabsorption
Augments production of 1,25-dihydroxyvitamin D in kidney
Augments renal phosphate excretion - PTH production
Decreased ionized serum Ca++ results in increased PTH production/secretion
Increased ionized serum Ca++ results in decreased PTH production/secretion
Increased 1,25-dihydroxyvitamin D feeds back to inhibit PTH production/secretion
Increased phosphate in blood directly stimulates PTH production and indirectly results in increased PTH because it binds ionized calcium (lowering ionized Ca++ levels)
Describe the production of active vitamin D. How is it inactivated?
- Production requires conversions in skin, liver and kidneys.
- 7-dehydrocholesterol converted to previtamin D3 in skin by ultraviolet light and then isomerized to vitamin D3.
- Vitamin D3 carried in blood via vitamin D-binding protein (VDBP).
- Liver is site of 25 hydroxylation.
- Dietary substrates [vitamin D2(plant sources) and vitamin D3 (animal sources)] delivered to liver
in portal circulation for 25-hydroxylation as well. - VDBP carries 25-(OH)D to kidneys where some of the 25-(OH)D is converted by 1-hydroxylation by 1-alpha-hydroxylase (Cyp1α) to the active hormone 1,25-(OH)2 D.
- Kidney and other tissues inactivate the majority of circulating 25-(OH)D by 24-hydroxylation (inactive form).
What is the mechanism of the vitamin D receptor? What overall effects does vitamin D have? What are 3 ways in which it accomplishes each one?
- 1,25-(OH)2 D actions:
Binds vitamin D receptor which then complexes with retinoid-X receptor and accessory coactivators. The VDR complex exerts transcriptional regulation of numerous genes after binding to the vitamin D response element.
1,25-(OH)2 D raises serum Ca++ levels
a. increases intestinal Ca++ absorption
b. increases bone resorption
c. can increase renal Ca++ absorption in vitamin D –deficient states
1,25-(OH)2 D raises serum PO4 levels
a. increases intestinal absorption
b. increases renal absorption
c. inhibits PTH production/secretion
What are the pharmacological effects of calcitonin and what is it used to treat? Where is it produced? What stimulates its secretion? What is its action?
- Physiologic role in humans unclear, but effective as a therapeutic in treatment of osteoporosis, hypercalcemia or Paget’s Disease (high bone turnover, bone pain, bone deformities). At high pharmacologic doses (parenteral or intranasal salmon calcitonin) may increase renal Ca++ excretion.
- Produced in C cells of the thyroid. (32 a.a.)
- Secretion stimulated by hypercalcemia and gastrin (?prevention of post-prandial hypercalcemia).
- Inhibits osteoclasts and decreases bone resorption (lowering serum Ca++).
What is the effect of estradiol on calcium/bone? What is the mechanism?
Estradiol
- Prevents bone resorption, increases renal Ca++ reabsorption, and augments intestinal Ca++ absorption.
- Postmenaopausal bone loss is a consequence of ovarian senescence.
- Mechanism
Possibly via sensitizing the mechanoreceptors in bone so that in the absence of estrogen, high levels of mechanical strain are required to stimulate new bone formation.
Possible direct effects on osteoblasts to increase survival
Decrease pre-osteoclast differentiation and osteoclast activity
What effects does testosterone have on calcium/bone? Mechanism?
Testosterone/Dihydrotestosterone
- Androgen deficiency, like estrogen deficiency, leads to rapid bone loss, which exogenous T
can reverse.
- Mechanism probably due to peripheral conversion of T to E (aromatase).
- T does increase width of bones, providing mechanical advantage.
What effects do glucocorticoids have on calcium/bone? Mechanism?
- Effects of endogenous glucocorticoids not significant because of compensatory mechanisms.
- Longterm glucocorticoid therapy (e.g. prednisone) causes bone loss by increasing bone
resorption, decreasing bone formation (mechanism may be by causing apoptosis of
osteoblasts and osteocytes).
What effects does GH have on calcium/bone? Mechanism?
- Increases bone remodeling, favors formation, leading to increased bone mass.
- Mechanism may be direct effect on osteblasts or indirect via stimulation of IGF-1
production in liver.
- GH deficiency results in low bone mass that responds to GH therapy.
- GH excess (e.g. acromegaly) actually have decreased (not increased as expected) bone mass probably due to these patients commonly being hypogonadal.
What effects does TH have on calcium/bone? Mechanism?
Thyroid Hormone
- T3 increases bone resorption and bone loss.
- Increases serum ionized Ca++ levels (results in lowered PTH, vitamin D)
What effects do local factors have on calcium/bone? Mechanism?
- After menopause up-regualtion of cytokines (IL-1, IL-6, TNF-α) promote osteoclast differentiation and increased bone resorption.
- RANK expression increases and OPG production decreases further driving osteoclast formation.
What effects does PTHrP have on calcium/bone? Mechanism?
- In malignant states PTHrP is overexpressed. (homologous structure in N-terminus to PTH)
- Exerts actions via the same receptors and similarly increases bone resorption (causes Hypercalcemia of Malignancy).
What effects does CaSR have on calcium/bone? Mechanism?
- Inactivating mutations of CaSR result in hypercalcemia (less inhibition of PTH release).
- Activating mutations result in hypocalcemia.
- In parathyroid gland increases in serum ionized Ca++ activate the CaSR, leading to lower PTH production/secretion (decreases result in the opposite).
- CaSR present on C cells of thyroid, where increased serum ionized Ca++ stimulates calcitonin release (decreases result in the opposite).
- Activation of CaSR in kidney (ascending limb of Henle) results in decreased Ca++ reabsorption.
- In bone CaSR mediates the inhibitory effect of local Ca++ levels on osteoclast function.
Describe what happens and how it happens when Calcium levels increase. What is the major factor?
- Increased calcium intake leads to small increments in serum ionized Ca++.
- Compensatory mechanisms activated:
PTH suppressed
1-25-(OH)2 D levels fall
Calcitonin released
Bone resorption decreases
Renal Ca++ excretion increases (decreased PTH, CaSR activation augments Ca++
excretion) *Kidney plays a major role in the compensation
Intestinal Ca++ absorption decreased
Describe what happens in hypocalcemia. What are the mechanisms at plahy? What is the major factor?
- In cases of inadequate dietary calcium intake.
- Increased fractional absorption of Ca++ in intestine.
- Hypocalcemia sensed by CaSR and PTH increases.
- 1-25-(OH)2 D levels rise
- Serum calcitonin suppressed.
- Resulting in increased intestinal Ca++ absorption, decreased renal Ca++ excretion, increased
bone resorption.
- Here all three tissues need to play a role in the compensation (not just kidney).
What happens with calcium in immobilization? Mechanisms? Same questions for exercise.
Increased bone resorption and decreased formation leads to incr. serum calcium leading to decr. PTH leading to less vit. D leading to decr. intestinal absorption.
Decreased bone resorption and increased bone formation leads to decreased serum calcium which leads to increased PTH which leads to increased Vit D which leads to increased intestinal absorption.
