Parathyroid hormone and Calcitonin Flashcards
1
Q
what is Rickets
A
softening and bending of the bones
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
3
Q
99% of calcium is found in ___
A
skeletal system (bone + teeth)
4
Q
1% of calcium is found _____ and 0.1% is found _____
A
intracellularly
extracellularly
5
Q
0.1% of extracellular calcium is found in plasma = ___ mg/dL
A
10 mg/dL
6
Q
50% of the 0.1% [____ mg/dL] is found in the ___ form
A
5mg/dL
free form
7
Q
which form of calcium is used for bones, teeth, or stored in ER
A
free form
8
Q
calcium can be found in bound form. what does it bind to?
A
- plasma proteins
- anions [bicarbonate, phosphate, lactate]
9
Q
____ cells produce parathyroid hormone PTH
A
chief cells
10
Q
what tiggers PTH release
A
PTH is released in response to low levels of ionized calcium in ECF
11
Q
function of PTH
A
PTH increased Ca in ECF
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
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
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
15
Q
what is CaR and where is it located
A
calcium sensing receptor located on cell membrane of chief cells
16
Q
signalling of CaR when there’s high [Ca] in ECF
A
decreased cAMP and increased IP3
17
Q
signalling of CaR when there’s low [Ca] in ECF
A
increased cAMP and decreased IP3 -> secretion of PTH
18
Q
what kind of receptor is the CaR
A
G-couple protein receptor GPCR
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
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
21
Q
PTH receptor is a ____
A
GPCR
22
Q
PTH signalling can be done through ____ and ____
A
cAMP -> PKA or PLC -> IP3 + DAG -> increase in calcium and PKC
23
Q
there is 3 PTH receptor isoforms. true or false?
A
false, there are 2 isoforms (1 and 2)
24
Q
PTH acts on 3 major tissue which are ______ to regulate calcium levels
A
bone, kidney, intestine
25
how does PTH increase ECF calcium by acting on bone tissue
PTH increases the resorption of bone by stimulating osteoclasts and promotes the release of calcium and phosphate into the circulation
26
how does PTH increase ECF calcium by acting on kidneys
PTH acts on collecting tubules in kidney to allow for calcium reabsorption from urine -> increase of calcium in ECF
27
which minerals make up bone
- calcium
- phosphate
- magnesium
28
which cells make up the bone
- osteoprogenitor cells [precursor cells for osteoblasts]
- osteoblasts [terminally differentiate into osteocytes]
- osteocytes
- osteoclasts
29
what are the 2 most important proteins present in bone matrix?
- osteocalcin secreted by osteoblasts
| - osteonectin secreted by fibroblasts
30
the two major proteins found in the bone matrix hep with ____ by binding to _____
calcification by binding to hydroxyapatite
31
what are the 3 major steps in bone formation
- 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
32
osteoblasts and osteocytes are linked through ____
canaliculi
33
bone resorption and bone re-synthesis (bone remodelling) requires _____
a precise balance
34
turn over calcium in bones ____ per year in infants and ____ in adults
100% in infants and 18% in adults
35
how does osteoblasts carry out calcification
they produce proteins and ECM and local growth factors for calcification to occur
36
which factors regulate balance between bone resorption and bone re-synthesis?
- 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
what can lack of exercise cause?
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
____ dissolve bone followed by _____ that lay down new bone
osteoclasts dissolve bone followed by osteoblasts that lay down new bone
39
mechanism of action of osteoclasts and bone degradation/release of calcium
- 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
_____ in urine is an index of bone resorption activity
pyridinoline (collagen breakdown product)
41
osteoclast bone degradation and calcium release is involved in acute regulation of calcium homeostasis. True or false
False, this is a slow process therefore any acute changes of calcium necessary for neuronal transmission or muscle contraction is regulated by PTH
42
osteoblasts secrete growth factors called ______ during bone remodelling
osteoclast activating factors
43
____ and _____ regulate bone remodelling and local growth factors involved
vitamin D and PTH
44
____ directly inhibits osteoclasts activity
calcitonin
45
____, ____, and ____ act on osteoblasts to produce osteoclast-activating factors
PTH, calcitriol [vitamin D], and PGE2
46
function of osteoclast-activating factors
stimulate bone-matrix resorption by osteoclast s
47
____ hormone can increase osteoclast activity
thyroid hormones
48
function of Parathyroid related protein PTHrP
required for normal development as a regulator of the proliferation and mineralization of chondrocytes and regulator of placental calcium transport
49
what is a problem that can be associated with PTHrP?
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
both PTH and PTHrP are produced by one type of cell. True or false?
False, PTH is only produced by chief cells but PTHrP is expressed by multiple cell types
51
PTHrP can only bind to isoform 1 of PTH receptor. true or false
True
52
what is osteopetrosis
"marble bone"; increase in bone density due to defective osteoclasts - over calcification - bones become more brittle and are prone to fracture
53
what is osteoporosis
excessive osteoclast function - frequent fractures due t weaker bones
54
what is involutional osteoporosis
loss of bone density with age
55
there are 2 phases with calcium metabolism in men and 3 phases in women. Explain
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
____ down-regulates osteoclast activity
estrogen
57
mechanism of estrogen on down-regulation of osteoclast activity
estrogen inhibits cytokines that stimulate the development of osteoclasts and stimulates cytokine TGF-beta that causes apoptosis of osteoclasts
58
what happens during menopause in regards to osteoclast activity
menopause -> estrogen levels decrease -> osteoclast activity increases
59
what characterizes primary hyperparathyroidism
increased parathyroid cell proliferation and PTH secretion which is independent of calcium levels
60
which genes could be involved in hyperparathyroidism
loss of tumor suppressor genes MEN1 and MEN 2A
61
what are the symptoms associated with increased PTH [hyperparathyroidism ]
- stones
- bones
- groans
- psychic moans
62
what are the causes of hypoparathyroidism
- failure to secrete PTH
- altered responsiveness to PTH
- Vitamin D deficiency or resistance to vitmin D
63
what is the major clinical symptom of hypoparathyroidism
increased neuromuscular excitability causing tetany
64
what is the treatment for hypoparathyroidism
calcium + vitamin D
65
mechanism causing tetany
- 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
____ an anticoagulant in blood transfusions can cause tetany
citrate
67
______ aka ____ produce calcitonin
parafollicular or C-cells
68
role of calcitonin
only known hormone that reduces serum calcium [hypercalcemia]
69
overproduction of calcitonin due to tumours of the parafollicular cells of the thyroid has dramatic phenotypic consequences. True or false?
false, there are NO phenotypic consequences even when there is a thyroidectomy
70
difference between calcitonin and CGRP
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
deficiency of ______ leads to bone defects and disease rickets
vitamin D
72
what is rickets
bone deformation and loss of calcium and phosphate from the bones - bone softening
73
how do you obtain vitamin D
from diet or synthesized by the skin through a photochemical reaction
74
how does vitamin D increase calcium absorption and in turn increase [Ca] ECF
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
which metabolite of vitamin D causes the physiological effects
calcitriol (1,25-(OH)2D3) [by-product of kidney]
76
mechanism of action of calcitriol
lipid soluble molecule that has nuclear receptor -> signaling occurs through transcriptional regulation and the target genes change the cellular function
77
all the steps in regulation of calcium through PTH/calcitonin/D3
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
what can cause vitamin D deficiency
inadequate sunlight, nutrition or malabsorption
79
consequences of vitamin D deficiency
abnormal mineralization of bone and cartilage (rickets, osteomalacia)
