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1,25-dihydroxycholecalciferol (1,25-(OH)2D3, _____) is a steroid hormone derivative of vitamin D3, formed with sunlight in the skin and subsequent processing in the liver and kidney. 1,25-(OH)2D3 enhances ________.
- calcitriol
- intestinal calcium absorption
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Parathyroid hormone (PTH) is a _______ hormone secreted by the parathyroid glands, which acts to ________. PTH is the key hormone responsible for regulating calcium levels within a very narrow range, and its secretion is directly controlled by ______.
- peptide
- elevate plasma calcium by mobilizing calcium from bone
- free plasma [Ca2+]
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Calcitonin is a _____ hormone, which is secreted by ______. It antagonizes the effect of _______.
- peptide
- parafollicular cells of the thyroid
- PTH and lowers plasma calcium levels
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There are three basic fractions of calcium in plasma:
- Ionized free Ca2+, ~ 50%.
- Calcium bound to extracellular proteins, most notably, albumin, almost half.
- Calcium complexed with other plasma ions and metabolites, particularly citrate and phosphate, 5-10%
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Ca2+ binding to proteins is sensitive to pH, because many of the primary carboxyl group binding sites have a pKa in the physiological range. As the pH increases, these become more ______, and Ca2+ binding affinity _______. Conversely, at more acidic pH, calcium binding affinity ______.
Therefore, acute acidosis ________ plasma free Ca2+ and acute alkalosis (hyperventilation) _______ plasma free Ca2+.
- fully deprotonated
- increases
- is reduced
- increases
- decreases
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The lowering of Ca2+ can lead to a _______ effect on nerve and muscle (due to enhanced Na+ permeability; Ca2+ interacts w/ Na chan, when Ca2+ is lower, the chan becomes more sensitive; when drops to half, fires spontaneously), leading to ______ that may be observed during respiratory ______.
- net excitatory
- hypocalcemic tetany
- alkalosis (hyperventilation)
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Most ingested calcium is eliminated from the body via _____.
The kidneys recover ~98% of filtered calcium, but _____ calcium is still excreted in urine.
_______ calcium is absorbed back back the intestine.
- the feces (850mg out of 1000mg per day)
- ~150 mg
- ~150 mg
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______ is the largest calcium reservoir (____), calcium in extracellular fluids (_____) and associated with cells (_____) is a minor component.
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More phosphate is absorbed from the gut (______) than calcium, and almost all of this is excreted in urine. The kidneys recover ____% of filtered phosphate.
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Most phosphate is in bone (_____), but soft tissue stores a substantial part of the total body pool (_____) and includes intracellular metabolites. These are in relatively rapid exchange equilibrium with plasma phosphate (_____). A major component of soft tissue phosphate is ______.
- 500g
- 84g
- 900mg
- the muscle mass
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Fundamentally, three types of cell involved in bone formation and resorption:
- Osteoblasts
- Osteoclasts
- Osteocytes
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Osteoblasts are the ______ cells that secrete the _______ (______, primarily _____) on which _______ precipitate to form the rigid ________ structure.
- bone-forming
- bone protein matrix
- osteoid
- collagen
- Ca2+ and PO4
- hydroxyapatite
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Osteoclasts are responsible for _______ and _______ of bone calcium. They are _______ cells.
- bone resorption
- the mobilization
- large multinucleate
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Osteocytes, the _____ bone cells are ______ the bone matrix.
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A relatively rapid transfer of calcium from bone _____ to the external surface of the bone, occurs by a process called _______, involving liberation of calcium from _______.
- canaliculi
- osteocytic osteolysis
- recently formed crystals
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The canaliculi give a very large _______ and provide ________ between the interior surface of the bone and extracellular fluid. Calcium and phosphate are transferred through _______ process that connect the ______ within the bone to surface cells, eventually liberating calcium to the plasma
- effective surface area
- an interface
- syncytial
- osteocytes
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The predominant mechanism of sustained calcium liberation from already formed bone is ________ mediated by _______, which ________. _______ are liberated. This process is important for bone _______, and for _______ under conditions of ______.
- the resorption
- Osteoclasts
- secrete collagenase, phosphatase, lysozomal enzymes and create an acidic environment that allow the osteoclast to “tunnel” into the bone
- Calcium, phosphate and amino acids
- remodeling
- the mobilization of calcium
- prolonged hypocalcemia
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In contrast to osteolysis, which extracts calcium without ______, resorption _______. During remodeling, osteoblasts lay down _____ and _______ resumes.
- loss of bone mass
- destroys the entire bone matrix and leads to loss of bone mass
- new matrix
- calcium phosphate mineralization
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_______ increase Ca2+ absorption from intestine
_______ increase Ca2+ deposition into bone
_______ increase Ca2+ resorption from bone
_______ increase Ca2+ resorption from kidney
_______ inhibit Ca2+ resorption from kidney
- 1,25-DHD3, PTH, prolactin
- calcitonin
- PTH, 1,25-DHD3, cortisol
- PTH
- calcitonin
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Vit D3 sources
- dietary
- 7-dehydrocholesterol ->-> vitD3 by UV in skin cells
-
Vit D3 activation
- involving distinct P450 hydroxylase enzymes in the liver and kidney
- The first hydroxylation: liver; yielding 25-hydroxycholecalciferol (25-(OH)D3).
- The second hydroxylation: kidney; 1α-hydroxylase; yielding the active form, 1,25-(OH)2D3.
- A distinct enzyme catalyzes the formation of 24,25-(OH)2D3 also in kidney, which is inactive. The formation of 24,25-(OH)2D3, may be a means to remove excess vitamin D3
-
Regulation of 1,25-(OH)2D3 synthesis
stimulators
inhibition
primary site of regulation
- PTH, Low levels of plasma calcium and phosphate
- feedback inhibition by elevated levels of 1,25-(OH)2D3, which then favors the formation of the inactive 24,25-(OH)2D3.
- The primary site of regulation of 1,25-(OH)2D3 level is in the kidney, through the activity of 1-α-hydroxylase.
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Circulating 1,25-(OH)2D3 (Vit D) is bound to the globulin, ______, with only a small fraction existing in free form.
transcalciferin (TC)
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Action of 1,25-(OH)2D3
- free form crosses the cell membrane and the nuclear membrane of target cells
- interacts with a vitamin D receptor (VDR)
- dimerization with the retinoic acid receptor (RXR)
- DNA binding
- interaction of receptors with transcription factors
- stimulation or inhibition of gene transcription
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Effects of 1,25-(OH)2D3 on calcium and phosphate homeostasis
- All major effects are mediated by steroid-like nuclear receptors -> gene transcription.
- stimulate the absorption and active transport of calcium from the intestine via stimulation of calcium uptake by increased expression of Ca2+-binding proteins and Ca2+-pumps.
- also increases active phosphate and magnesium absorption by the intestine.
- acts on the parathyroid gland to reduce PTH synthesis.
- Complex in bone: enhances the effects of PTH on bone resorption, possibly through recruitment of osteoclasts; required for normal mineralization of bone, through the supply of calcium and phosphate -> deficiency associated with rickets - weakness and bowing of weight-bearing bones.
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Ca2+ enters microvilli of the brush border through ______, moving down its concentration gradient into the cell cytoplasm.
Ca2+ diffusion through the enterocyte is facilitated by Ca2+ binding proteins (_________).
Ca2+ is actively transported across the basolateral membrane by _______.
1,25-(OH)2D3 increases the expression level of _________, thereby enhancing Ca2+ absorption.
- calcium channels
- Calbindin
- Ca2+ pumps
- these Ca2+ channels, pumps and binding proteins
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PTH is a ______ hormone synthesized and secreted by _______ of the parathyroid gland.
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PTH is initially translated as a _______. Cleavage of ______ yield a biologically active peptide of __ amino acids, which is stored in secretory granules.
Further cleavage may occur in _______ to yield __ AA N-terminal fragment with biological activity, and _____.
- pre-prohormone
- leader and pro-sequences
- 84
- the gland or the periphery
- 34
- an inactive C-terminal fragment
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PTH release is under the control of ______, through a _______.
The half-life of circulating PTH is about ___
- plasma Ca2+
- “Ca2+- sensing” receptor
- 10 min.
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The plasma concentration of Ca2+ is detected by a unique _______ on the cell surface of the ____ cells.
High Ca2+ activates the receptor to stimulate _______ and inhibits _______, together these cause ______.
The reverse occurs when the extracellular Ca2+ is low. The receptor is no longer active, ______ decrease and _____ increases. This leads to ________.
- Gprotein-coupled calcium receptor (CaR, Gq and Gs)
- chief
- phospholipase C (PLC) to generate IP3 and diacylglycerol (DAG), which leads to increase cytosolic Ca2+
- adenylate cyclase (AC) and reduces cAMP generation
- inhibition of PTH secretion
- IP3 and cytosolic Ca2+ levels
- cAMP
- stimulation of PTH secretion
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Secretion of PTH is ______ related to plasma [Ca2+]. Secretion of PTH is maximal when plasma [Ca2+] falls below ____ and is at a minimum when plasma [Ca2+] increases above ___. Thus, PTH secretion is controlled in _____, with 90% of the range of PTH release occurring with less than 10% (0.1 mM range) variation in plasma [Ca2+].
- inversely
- ~1.2 mM
- 1.3 mM
- a very narrow range of plasma [Ca2+]
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Other effectors of PTH secretion:
Inhibitor:
Stimulators:
- 1,25-(OH)2D3 at gene transcription level
- agents that elevate cAMP in the Chief Cell, including epinephrine, histamine and dopamine.
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Parathyroid hormone (PTH) actions
GsPCR -> adenyl cyclase (AC) -> cAMP -> stimulates signal transduction processes that activate various functions in bone cells and kidney tubular cells.
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The overall effect of PTH is to _______ and _______.
- increase plasma Ca2+ levels
- reduce plasma phosphate levels
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PTH In Bone:
- stimulates osteolysis (osteocyte-dependent transport of calcium out of bone canalicular fluid).
- stimulates bone resorption by osteoclasts, liberating calcium and phosphate and causing bone destruction.
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PTH receptors are present on _______.
PTH activates osteoclasts indirectly through _________.
- osteoblasts and osteocytes
- paracrine factors released by osteoblasts (RANKL)
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PTH In Kidney:
calcium
phosphate
vit d3
- • PTH stimulates calcium reabsorption in the distal tubule of the kidney, enhancing recovery of filtered calcium.
- • PTH inhibits phosphate reabsorption, thereby stimulating phosphate excretion. This is important to eliminate excess phosphate generated by bone resorption.
- • PTH stimulates synthesis of 1,25-(OH)2-D3. This has the indirect effect of increasing intestinal calcium and phosphate absorption.
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Calcitonin is a ______ hormone secreted by _______ of the thyroid gland. Its primary effect is to ________ and is less critical than PTH and 1,25-(OH)2D3 in ________.
- peptide
- the parafollicular cells (C-cells)
- reduce plasma Ca2+
- regulating calcium homeostasis
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Calcitonin secretion is stimulated by _____.
The major mechanism of calcitonin action is to __________.
While the effect of calcitonin is opposite to PTH on plasma calcium, it has a similar effect to PTH to _______.
- elevated plasma Ca2+
- antagonize the effects of PTH on bone by inhibiting osteoclast-mediated bone resorption
- reduce plasma phosphate and increase urinary phosphate excretion
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The net effect of PTH actions is _______ and ________, combined with _______ and ________.
- hypercalcemia
- hypophosphatemia
- hypocalciuria
- hyperphosphaturia
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The main action of 1,25-(OH)2D3 is to _______ in the gut, ______ in the kidney, and _____ on bone. Its production is increased by ________ and by ________.
- increase Ca2+ and phosphate absorption
- increase Ca2+ and phosphate resorption
- synergize with PTH
- a reduction in circulating calcium or phosphate
- increased PTH
-
calcitonin
- stimed by high [Ca]
- lower plasma [Ca] and phosphate
- inhibit bone resorption
- inhibit kidney Ca and phosphate reorption
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When there is a prolonged net excess of osteoclast bone resorption over osteoblast bone deposition, ______ results. This is most common in _____ women, and is due primarily to ______, which leads to elevated levels of cytokines that stimulate ______. Other causes include _______, most notably in _______.
- osteoporosis
- post-menopausal
- estrogen deficiency
- bone resorption
- inactivity
- the low-gravity associated with space flight
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Vitamin D deficiency can lead to _______ of the bone matrix, primarily due to _______ for normal mineralization. In children, vitamin D deficiency is associated with ____, characterized by ___________.
- defective calcification
- insufficient calcium and phosphate
- rickets
- weakness and bowing of weight-bearing bones, defects of the teeth and hypocalcemia
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In primary hyperparathyroidism, there is ________ leading to ______. Most often caused by ________. Relatively modest symptoms because high calcium overcomes some of the more damaging effects of excess PTH. May lead to ________.
- excess PTH secretion
- hypercalcemia
- benign parathyroid neoplasm (adenoma) that secretes PTH
- kidney stones
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Secondary hyperparathyroidism can result from _______, such as can occur in _____ and _______. Low levels of plasma Ca2+ cause chronic stimulation and hypertrophy of the parathyroid glands. PTH levels are ___, but plasma calcium is ___.
- chronic hypocalcemia
- renal disease
- vitamin D deficiency (rickets)
- high
- low
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Primary hypoparathyroidism most commonly results from ________. It can also be caused by ________ to the parathyroid gland. Hypoparathyroidism is characterized by __________. As noted above, this can lead to _________.
- inadvertent removal of the parathyroid glands during thyroid surgery
- autoimmune damage
- low levels of PTH, hypocalcemia and hyperphosphatemia
- nerve and muscle hyperexcitability and hypocalcemic tetany
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