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Metabolic Endocrinology > Parathyroid hormone and Calcitonin > Flashcards

Parathyroid hormone and Calcitonin Flashcards

1
Q

what is Rickets

A

softening and bending of the bones

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2
Q

what are the various roles of calcium (7)

A
  • major structural component of the skeleton [fundamental function, skeletal structure]
  • blood clotting [cross-linking of fibrin]
  • regulation of enzyme activities
  • “second messenger” of hormone signals (GPCR -> IP3, released from ER)
  • membrane excitability
  • muscle contraction
  • hormone secretion
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3
Q

99% of calcium is found in ___

A

skeletal system (bone + teeth)

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4
Q

1% of calcium is found _____ and 0.1% is found _____

A

intracellularly

extracellularly

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5
Q

0.1% of extracellular calcium is found in plasma = ___ mg/dL

A

10 mg/dL

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6
Q

50% of the 0.1% [____ mg/dL] is found in the ___ form

A

5mg/dL

free form

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7
Q

which form of calcium is used for bones, teeth, or stored in ER

A

free form

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8
Q

calcium can be found in bound form. what does it bind to?

A
  • plasma proteins

- anions [bicarbonate, phosphate, lactate]

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9
Q

____ cells produce parathyroid hormone PTH

A

chief cells

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10
Q

what tiggers PTH release

A

PTH is released in response to low levels of ionized calcium in ECF

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11
Q

function of PTH

A

PTH increased Ca in ECF

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12
Q

steps in synthesis of PTH

A
  • signal peptide (25a) from pre-pro-hormone is cleaved in ER
  • 6 aa pro sequence is cleaved in Golgi
  • 84 aa mature sequence is stored in granules
  • granules contain mature PTH and proteases Cathepsin B and H
  • portion of PTH is cleaved to yield carboxylate terminus fragment
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13
Q

what happens during hypercalcemia regarding PTH regulation

A

stored PTH is mostly as fragments due to cathepsin. If Ca concentration is high in ECF, there will be PTH cleavage by cathepsin so there’s lower amounts of active PTH

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14
Q

how is PTH secretion regulated by calcium?

A
  • high [Ca] in ECF: Ca binds to Calcium sensing receptor (CaR) which leads to inhibition of pTH secretion
  • low [Ca] ECF: calcium not bound to CaR - no inhibition - PTH is secreted leading to increased [Ca] ECF
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15
Q

what is CaR and where is it located

A

calcium sensing receptor located on cell membrane of chief cells

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16
Q

signalling of CaR when there’s high [Ca] in ECF

A

decreased cAMP and increased IP3

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17
Q

signalling of CaR when there’s low [Ca] in ECF

A

increased cAMP and decreased IP3 -> secretion of PTH

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18
Q

what kind of receptor is the CaR

A

G-couple protein receptor GPCR

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19
Q

what are the different alpha subunits involved with CaR and what are their roles? (3)

A
  • Gs-alpha: stimulates cAMP
  • Gi-alpha: inhibits cAMP
  • Gq-alpha: targets PLC which synthesizes IP3
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20
Q

CaR are present on _____ that produce ____. CaR senses _____ and regulate ____ secretion

A

CaR are present on chief cells that produce PTH. CaR senses ECM calcium and regulate PTH secretion

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21
Q

PTH receptor is a ____

A

GPCR

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22
Q

PTH signalling can be done through ____ and ____

A

cAMP -> PKA or PLC -> IP3 + DAG -> increase in calcium and PKC

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23
Q

there is 3 PTH receptor isoforms. true or false?

A

false, there are 2 isoforms (1 and 2)

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24
Q

PTH acts on 3 major tissue which are ______ to regulate calcium levels

A

bone, kidney, intestine

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25
Q

how does PTH increase ECF calcium by acting on bone tissue

A

PTH increases the resorption of bone by stimulating osteoclasts and promotes the release of calcium and phosphate into the circulation

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26
Q

how does PTH increase ECF calcium by acting on kidneys

A

PTH acts on collecting tubules in kidney to allow for calcium reabsorption from urine -> increase of calcium in ECF

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27
Q

which minerals make up bone

A
  • calcium
  • phosphate
  • magnesium
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28
Q

which cells make up the bone

A
  • osteoprogenitor cells [precursor cells for osteoblasts]
  • osteoblasts [terminally differentiate into osteocytes]
  • osteocytes
  • osteoclasts
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29
Q

what are the 2 most important proteins present in bone matrix?

A
  • osteocalcin secreted by osteoblasts

- osteonectin secreted by fibroblasts

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30
Q

the two major proteins found in the bone matrix hep with ____ by binding to _____

A

calcification by binding to hydroxyapatite

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31
Q

what are the 3 major steps in bone formation

A
  • osteoblasts secrete collagen and other proteins to form a matrix (osteoid)
  • mineralization (deposition of hydroxyapatite) in two stages: primary mineralization [60-70%] in 6-12h followed by secondary mineralization in 1-2 months
  • entombed osteoblasts differentiate into osteocytes=> formation of a network of metabolically active cells
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32
Q

osteoblasts and osteocytes are linked through ____

A

canaliculi

33
Q

bone resorption and bone re-synthesis (bone remodelling) requires _____

A

a precise balance

34
Q

turn over calcium in bones ____ per year in infants and ____ in adults

A

100% in infants and 18% in adults

35
Q

how does osteoblasts carry out calcification

A

they produce proteins and ECM and local growth factors for calcification to occur

36
Q

which factors regulate balance between bone resorption and bone re-synthesis?

A
  • mechanical factors [use of skeleton]
  • hormonal factors induced by PTH
  • paracrine factors (ie. IGF-II produced by osteoblasts [local growth factors]) may act on neighbouring osteoblasts and osteoclasts
37
Q

what can lack of exercise cause?

A

lack of exercise is associated with osteomalacia - condition where there’s abnormal deposition of calcium => over calcification of certain parts of bone - highly prone to breakage

38
Q

____ dissolve bone followed by _____ that lay down new bone

A

osteoclasts dissolve bone followed by osteoblasts that lay down new bone

39
Q

mechanism of action of osteoclasts and bone degradation/release of calcium

A
  • attach to bone via integrins and form tight seal
  • protein pumps move from endoscopes to the cell membrane where they pump out protons
  • acid pH 4.0 dissolves hydroxyapatite; acid proteases break down collagen
  • breakdown of ECM protein will cause calcium to be released [attached]
  • transcytosis through osteoclasts of degradation product and release into interstitial fluid [from ECM to ECF]
40
Q

_____ in urine is an index of bone resorption activity

A

pyridinoline (collagen breakdown product)

41
Q

osteoclast bone degradation and calcium release is involved in acute regulation of calcium homeostasis. True or false

A

False, this is a slow process therefore any acute changes of calcium necessary for neuronal transmission or muscle contraction is regulated by PTH

42
Q

osteoblasts secrete growth factors called ______ during bone remodelling

A

osteoclast activating factors

43
Q

____ and _____ regulate bone remodelling and local growth factors involved

A

vitamin D and PTH

44
Q

____ directly inhibits osteoclasts activity

A

calcitonin

45
Q

____, ____, and ____ act on osteoblasts to produce osteoclast-activating factors

A

PTH, calcitriol [vitamin D], and PGE2

46
Q

function of osteoclast-activating factors

A

stimulate bone-matrix resorption by osteoclast s

47
Q

____ hormone can increase osteoclast activity

A

thyroid hormones

48
Q

function of Parathyroid related protein PTHrP

A

required for normal development as a regulator of the proliferation and mineralization of chondrocytes and regulator of placental calcium transport

49
Q

what is a problem that can be associated with PTHrP?

A

it usually acts in paracrine fashion but over expression by tumor cells can produce severe hypercalcemia by activating PTH receptor. Indeed PTHR-1, located in bone and kidney tissues can bind PTH and PTHrP with equal affinity

50
Q

both PTH and PTHrP are produced by one type of cell. True or false?

A

False, PTH is only produced by chief cells but PTHrP is expressed by multiple cell types

51
Q

PTHrP can only bind to isoform 1 of PTH receptor. true or false

A

True

52
Q

what is osteopetrosis

A

“marble bone”; increase in bone density due to defective osteoclasts - over calcification - bones become more brittle and are prone to fracture

53
Q

what is osteoporosis

A

excessive osteoclast function - frequent fractures due t weaker bones

54
Q

what is involutional osteoporosis

A

loss of bone density with age

55
Q

there are 2 phases with calcium metabolism in men and 3 phases in women. Explain

A

there is a rapid increase of bone mass to young adult levels (phase 1) followed by a steady loss of bone with advancing age in both sexes (phase 3) and the superimposed rapid loss in women after menopause (phase 2)

56
Q

____ down-regulates osteoclast activity

A

estrogen

57
Q

mechanism of estrogen on down-regulation of osteoclast activity

A

estrogen inhibits cytokines that stimulate the development of osteoclasts and stimulates cytokine TGF-beta that causes apoptosis of osteoclasts

58
Q

what happens during menopause in regards to osteoclast activity

A

menopause -> estrogen levels decrease -> osteoclast activity increases

59
Q

what characterizes primary hyperparathyroidism

A

increased parathyroid cell proliferation and PTH secretion which is independent of calcium levels

60
Q

which genes could be involved in hyperparathyroidism

A

loss of tumor suppressor genes MEN1 and MEN 2A

61
Q

what are the symptoms associated with increased PTH [hyperparathyroidism ]

A
  • stones
  • bones
  • groans
  • psychic moans
62
Q

what are the causes of hypoparathyroidism

A
  • failure to secrete PTH
  • altered responsiveness to PTH
  • Vitamin D deficiency or resistance to vitmin D
63
Q

what is the major clinical symptom of hypoparathyroidism

A

increased neuromuscular excitability causing tetany

64
Q

what is the treatment for hypoparathyroidism

A

calcium + vitamin D

65
Q

mechanism causing tetany

A
  • hyperventilation will cause decreased CO2 concentration which reduces carbonic acid and in turn bicarbonate and protons causing alkalosis
  • to compensate, protons are released from serum proteins and the negatively changed proteins will bind calcium
  • reduction in free serum calcium will cause tetany (spasm of skeletal muscle)
66
Q

____ an anticoagulant in blood transfusions can cause tetany

A

citrate

67
Q

______ aka ____ produce calcitonin

A

parafollicular or C-cells

68
Q

role of calcitonin

A

only known hormone that reduces serum calcium [hypercalcemia]

69
Q

overproduction of calcitonin due to tumours of the parafollicular cells of the thyroid has dramatic phenotypic consequences. True or false?

A

false, there are NO phenotypic consequences even when there is a thyroidectomy

70
Q

difference between calcitonin and CGRP

A

thyroid C-cells produce calcitonin where as calcitonin gene related protein is made by neuronal cells
CT has 1,2,3,4 exon where as CGRP has 1,2,3,5,6 exon

71
Q

deficiency of ______ leads to bone defects and disease rickets

A

vitamin D

72
Q

what is rickets

A

bone deformation and loss of calcium and phosphate from the bones - bone softening

73
Q

how do you obtain vitamin D

A

from diet or synthesized by the skin through a photochemical reaction

74
Q

how does vitamin D increase calcium absorption and in turn increase [Ca] ECF

A

vitamin D is converted in the liver to 25-hydroxyvitamin D2 or D3 which is further metabolized in the kidney to 1,25-dihydroxyvitamin D2 or D3 [calcitriol] which acts on the intestine to increase calcium absorption

75
Q

which metabolite of vitamin D causes the physiological effects

A

calcitriol (1,25-(OH)2D3) [by-product of kidney]

76
Q

mechanism of action of calcitriol

A

lipid soluble molecule that has nuclear receptor -> signaling occurs through transcriptional regulation and the target genes change the cellular function

77
Q

all the steps in regulation of calcium through PTH/calcitonin/D3

A

homeostasis: blood calcium level 10mg/dL
- stimulus: rising blood calcium level -> thyroid gland releases CALCITONIN -> stimulates calcium deposition in bones and reduces calcium uptake in kidneys -> blood calcium level declines to set point
- stimulus: falling blood calcium level -> parathyroid gland -> PTH -> stimulates calcium release from bones, stimulates calcium uptake in kidneys, stimulates vitamin D conversion in kidney to active vitamin D which stimulates calcium uptake in intestines -> blood calcium level rise to set point

78
Q

what can cause vitamin D deficiency

A

inadequate sunlight, nutrition or malabsorption

79
Q

consequences of vitamin D deficiency

A

abnormal mineralization of bone and cartilage (rickets, osteomalacia)

Metabolic Endocrinology (10 decks)

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