Ca metabolism Flashcards
Is there a circadian rhytms for thyroid hormone
We have confirmed that in humans there is a circadian rhythm of TSH with a peak level occurring at around 02:40 h and levels remaining above the mesor from 20:20–08:20 h
How regulation of calcium with PTH/D3 occurs
Regulation of calcium via calcitonin
Do we know the role of calcitonin
No, uncertain
What are remedies for rickets
Fish liver oil
Sun exposure
UV-irradiation of certain foods
Roles of Ca
- v Major structural component of the skeleton
- Blood clotting (cross-linking of fibrin)
- Regulation of enzyme activities (induction of conformational changes or co-factor)
- “Second messenger” of hormones signals .Release from endoplasmic reticulum
- Membrane excitability
v Secretion of hormone/neurotransmitters
v Action potential
- Muscle contraction
v Triggered by the release of Ca++ from the
sarcoplasmic reticulum.
Where the most Ca is found and how extracellular Ca can be regulated
Extracellular and
Intracellular Ca++
levels are tightly
regulated
Skeleton 99%
Disequilibrium between bound and unbound
Ca++ causes ___
tetany
what is alkalosis
Hyperventilation
reduces the partial
pressure of CO2. Less
H2CO3 is produced and
H+ falls → alkalosis
How hyperventilation and tetany are connected
v Hyperventilation
reduces the partial
pressure of CO2. Less
H2CO3 is produced and
H+ falls → alkalosis
v To compensate H+ is
released from serum
proteins. The negatively
charged protein binds
Ca++
Reduction in free serum Ca++ → tetany (spasm of skeletal muscle)
v similarly, blood transfusions in which citrate is the anti-coagulant can
cause tetany (due to Citrate chelating Ca++)
How many thyroid glands are there
4
Can be 5 th in 15% of people
What cells produce PTH and when PTH is release
v Chief cells (and oxyphil cells)
produce Parathyroid Hormone
(PTH)
v PTH is released in response to
low levels of ionized Ca in ECF
Calcitonin action
Reduces serum Ca
Half life for PTH, how it is cleaved
v Highly conserved
v Short half-life
v 2-4 min
v Cleaved into two
fragments (amino and
carboxy terminus)
How chief cells react on Ca concentration in the blood
calcium sensing receptor (CaR) located on Chief
cell membrane of chief cells detect ECF Ca++
Ca receptros are ___ receptros and couple with
Ca receptors on the parathyroid
cells
vSeven-transmembrane domain
receptor
v Coupled with G-protein complex
vHighly conserved
What happens to parathyroid cells with Ca concentration alteration
v Concentration- dependent
conformation alteration
vHigh Ca concentrations –
Decreased cAMP and increased IP3
vLow Ca concentrations – Increased
cAMP and decreased IP3
v PTH functions to
regulate calcium
levels via its actions
on three target
organs___
– the bone,
kidney, and gut.
How PTH influences bones
PTH increases the
resorption of bone
by stimulating
osteoclasts and
promotes the
release of calcium
and phosphate into
the circulation.
Mineral content of bones
v 99% of total Ca+2
v 90% of total PO4-3
v 50% of total Mg+2
Cells in bone
v Osteoprogenitor cells
v Osteoblasts
v Osteocytes
v Osteoclasts
Organic matrix of bone: composition
v Collagen (90-95%)
v Proteoglycans
v Glycoproteins
v Lipids
Osteobalsts function
v1mg of osteocalcin
binds 17 mg of
hydroxyapatite
vSerum level is indicator
of bone growth.
Osteonectin function
vBinds collagen and
hydroxyapatite
vMay serve as nucleator
for calcium deposition
in the bone.
structure of bone
Describe osteoblast differentiation
Bone formation process describe
Turn-over Ca2+ in bone is ___per year in
infants and 18% in adults
100%
Bone remodelling is performed by
Carried out by bone modeling units:
osteoclasts dissolve bone followed by
osteoblasts that lay down new bone
Factors regulating remodeling
Mechanical factors
v Hormonal factors induced by PTH
v Paracrine factors (i.e. IGF-II produced by
osteoblasts) may act on neighboring
osteoblasts and osteoclasts
Osteoclasts are derived from
from monocytes (Bone marrow, gives rise to macrophages).
How ostoclasts are attached to bone
via integrins and form tight seal
How osteoclast reach acid pH
Proton pumps (H+ dependent ATPases) move from
endosomes to the cell membrane where they pump out
H+
v Acid pH (~ 4.0) dissolves hydroxyapaptite; acid
proteases break down collagen
What pyridinoline indicates
(collagen breakdown product) in urine is an
index of bone resorption activity
How many nuclei are there in osteoclasts
Multiple
Why osteoclasts are tightly bound to bone matrix
Permitting acid from ruffled apical membrane to resort the bone
Bone remodelling and its hormonal control
What inhibits osteoclast activity
Calcitonin
What stimulates osteoblast activity
PTH, calcitriol, PGE2 (prostaglandin E) act on osteoblast to produce osteoclast-activating factors that stimulate resoprtion by osteoclast
How PTH influencec renal system
PTH also increases renal reabsorption of Ca from 33
urine and inhibits reabsorption
of phosphate
What is the difference between PTH and PTHrP
Parathyroid Related Protein (PTHrP) similar structure to PTH and can bind to PTH receptor but produced by many tissues in fetus and adult
Function for PTHrP
required for normal development as a regulator of the
proliferation and mineralization of chondrocytes and regulator of
placental Ca++ transport
usually acts in paracrine fashion but overexpression by tumour
cells can produce severe hypercalcemia by activating PTH receptor
How many receptors for PTH and can PTHrP bind to it
2 G protein coupled receptors for PTH
PTHR-1 binds PTH and PTHrP with equal affinity
PTHR-2 binds only PTH
receptors have different tissue distributions
PTHR-1 is located in bone and kidney tissues
What is oteopetrosis
vOsteopetrosis: “marble bone”
vIncrease in bone density due to defective osteoclasts
– bones become more brittle and are prone to
fracture
Osteoporosis is
vExcess osteoclast function vFrequent fractures (areas with trabecular bone: distal forearm, vertebral body, hip)
What is involutional osteoporosis
vLoss of bone density with age
Do women has an increased bone loss?
How estrogen downregulates osteoclast activity and what happens with menopause and can estrogen therapy help with it
What is primary hyperthyroidism
Primary hyperparathyroidism is characterized by
increased parathyroid cell proliferation and PTH
secretion which is independent of calcium levels.
Etiology unknown, but radiation exposure, and lithium
implicated, associated with loss of tumor suppressor
genes (MENIN) MEN1 and MEN 2A
Enlargement of a single gland or parathyroid adenoma
in approximately 80% of cases, multiple adenomas or
hyperplasia in 15 to 20% of patients and parathyroid
carcinoma in 1% of patients
Signs and symptoms of primary hyperparathyroidism
Hypoparathyroidism may originate from
Problems with PTH may arise from
-failure to secrete PTH,
v altered responsiveness to PTH, Vit. D deficiency or
v a resistance to Vit. D
problems with PTH may arise from:
v surgery
v familial causes
v autoimmune disorders
v idiopathic causes
Major clinical symptoms of hypothyroidism and treatment
major clinical symptom is increased
neuromuscular excitability (tetany)
treatment: Calcium + Vitamin D
Treatment for hypercalcaemia
calcitonin
Is calcitonin physiologically important?
Overproduction of calcitonin (tumors of the parafollicular cells of the thyroid) → no phenotypic consequences
v Thyroidectomy → no phenotypic consequences
Is there only one calcitonin
From the same gene as calcitonin neuronal cells can produce calcitonin gene
related protein
may act as a neurotransmitter
v CGRP also acts as very
potent vasodilator via
GPCR receptor
Vitamin D defects leads to
vDeficiency leads to bone defects and the disease “rickets”,
which causes bone deformations and loss of calcium and
phosphate from the bones
How vitamin D can be formed from the skin
vVitamin D can be formed in the skin from 7-dehydrocholesterol
in a photochemical reaction requiring sunlight.
vVitamin D is converted in the liver and kidney to a hormone
that regulates calcium uptake.
How vitamin D is synthesized ( the form that is added to food)
Vitamin D2 is a
pharmaceutical product
made by irradiating
ergosterol (present in
some plants). Used in
food fortification such as
margarine and milk
what are the main circulating derivatives of vitamin D
Main circulating derivatives are 25-OHcholecalciferol
(made in the liver; 3-30 ng/ml) and
calcitriol (made in the kidney; 20-60 pg/ml)
Vitamin D binding protein binds what type of protein
Vitamin D binding protein present in the serum
binds 25-OH-cholecalciferol and to a lesser extent
calcitriol
All physiological effects appear to be due to what form of vitamin D
calcitriol
Calcitriol: where is the receptor and what is the function
How vitamin D promotes Ca absorption
Calcitriol promotes active
Ca2+ uptake in the intestine
by maintaining a Ca2+
gradient
v Uptake of calcium→binding to
myosin/calmodulin complex→
move to the bottom of the
microvilli driven by differential
binding to proteins → free
Ca2+ in cytoplasm is released
by exocytosis or pumps
v Calcitriol induces synthesis of
the calbindin protein→ binds
Ca2+→ maintenance of the
Ca2+ gradient by mopping up
all the free at the bottom of
the microvilli.
Interaction of PTH
and vitamin D in
controlling plasma
calcium
How can you get vitamin D deficiency and what diseases will occur
vinadequate sunlight, nutrition or malabsorption (up to
50-60 % of elderly expecially if institutionalized)
vcause abnormal mineralization of bone and cartilage
vRickets (children)
vOsteomalacia (adults)
How vitamin D toxicity can occur, symptoms and treatment
Overdose either therapeutically or accidently
Symptoms: weakness, lethargy, headaches, nausea, polyureia
due to hypercalcemia and hypercalciuria – may lead to ectopic
calcification etc. (kidneys, blood vessels, heart, lungs, skin)
with chronic overuse
v Treatment: reduced calcium intake and (Vit. D), rehydration
and cortisol (antagonizes action of Vit. D on gut absorption of
calcium) + time (slowly cleared from the body)
