Mineral metabolism Flashcards
Describe the Diurnal rhythm of T3/T4/TSH
TSH- concentrations are highest midnight to early morning
T3 and T4 don’t really have a rhythm
Where is T3/T4 made?
Which is made in bigger quantity?
T4 is made in follicular cells of thyroid
T3 is not only made by thyroid follicles; Deiodinases are spread all over the body
Type 1 and 2 convert T4 into T3-> peripheral tissues also contribute to T3 concentrations
T4 is produced in larger quantities than T3
T4 vs T3: affinity for binding; free form; half life; signalling
- Affinity for binding: T4>T3
- Free form: T3>T4
- Only free form is capable of signalling-> Free T3 are higher-> more signalling by T3; but T4 has longer half life
- Half life: T4>T3
Which organ senses the changes in calcium levels in the body? What is the response?
Parathyroid gland; releases parathyroid hormone (PTH) into the circualtion
Which organs does PTH act upon? What is the effect?
it can act upon 3 different organs systems: bones, kidney and intestines
1) In bones it increases bone resorption and increases Ca release into the circulation
2) In kidneys, it allows to retain Ca2+ and promotes activation of an inactive form of Vit D to calcitriol, an active form of Vit D
3) Small intestine increases absorption of more Ca from diet
Overall effect: increase Ca levels in the blood
This increased levels is senses by parathyroid gland-> less parathyroid hormone is released
Which cells release calcitonin? Where are they found?
C-type cells (clear cells) of thyroid gland are parathyroid cells (which means that they are outside of follicles
They produce calcitonin
What is the effect of calcitonin?
What is the stimuli for calcitonin secretion?
- Stimulates Ca deposition in bones
- Reduces Ca uptake in kidneys
Overall effect: Ca levels in the circulaiton decrease
Stimuli: rising blood Ca level
What is the Physiological role of calcitonin in humans ?
Physiological role of calcitonin in humans is uncertain
When was rickets first described?
Rickets was described in children (softening and bending of the bones)
What are the remedies for rickets?
Fish liver oil
Sun exposure
UV-irradiation of certain foods
WHat is the active ingredient that result in alleviation of rickets?
Where is it found, what is it’s function and how is it activated>
Vitamin D (collective term of a series of related compounds). Promotes absorption of calcium from the gut
Present in fish liver oil
Inactive precursors can be activated by UV
what are the roles of calcium (6)?
- 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
- Membrane excitability
- Muscle contraction
How does Ca act as a second mesenger of hormone signals?
- GPCR/IP3
Release of hormones from endoplasmic reticulum
How does Ca participate in membrane excitability?
- via Ca linked channels
- Secretion of hormone/neurotransmitters
- Action potential
How does Ca act in muscle contraction?
Triggered by the release of Ca++ from the sarcoplasmic reticulum.
Compartements that store Ca, and the % of total Ca stored in each of them
Which compartment is regulated as the overal impact of hormones
Skeleton (99%)
Intracellular (1%)
Extracellular (0.1%)- regulated as the overal impact of hormones
__ Ca++ levels are tightly regulated
Extracellular and Intracellular Ca++ levels are tightly regulated
Which Ca is the most important?
How is it controlled?
The non-complexed Ca++ is readily available and hence is the most important
Controlled by Vit D and PTH
What % of plasma calcium is ionized (free) calcium
45%
What are the types of bound plasma calcium?
- Plasma proteins (45%)
- Anions
Disequilibrium between bound and unbound Ca++ causes __
Disequilibrium between bound and unbound Ca++ causes tetany
How doe Disequilibrium between bound and unbound Ca++ cause tetany?
E.g. hyperventilation
In hyperventilation, a lot of CO2 is exhaled-> bicarbonate concentrations go down
reduced bicarbonate leads to reduced proton concentration → alkalosis; which causes serum proteins to release their protons to compensate for it
This makes proteins negatively charged -> look for positive ions-> bind positively charged calcium
Since calcium concentration in the circulation are so small, any small change leads to big consequences
Reduction in free serum Ca++ → tetany (spasm of skeletal muscle)
What else, apart from hyperventialtion, can cause tetany?
similarly, blood transfusions in which citrate is the anti-coagulant can cause tetany (due to Citrate chelating Ca++)
Where is Ca stored in the cells?
Stored in the sarcoplasm
Describe the make up of parathyroid glands
Which part secrets PTH? When?
v 4 glands (about 40 mg each) located adjacent to thyroid
v about 15 % of people have a 5th gland
v Chief cells (and oxyphil cells) produce Parathyroid Hormone (PTH)
v PTH is released in response to low levels of ionized Ca in ECF
Which cells produce calcitonin?
Parafollicular or C-cells produce calcitonin
Describe steps of PTH production
- produced as a pre-prohormone
- removal of signalling peptide which occurs as translation occurs converts it to pro-PTH
- with cleavage of first few fragments-> active parathyroid hormone
- Parathyroid hormones are stored in granules
PTH is __ conserved
PTH is Highly conserved
Does PTH have a short or long half life?
Short (2-4 min)
What are the fragments PTH is cleaved into?
Cleaved into two fragments (amino and carboxy terminus)
Regulation of PTH secretion by Ca++
- calcium sensing receptor (CaR) located on Chief cell membrane of chief cells detect ECF Ca++
- Levels of Ca regulate the shape of the receptor
- High Ca concentrations – Decreased cAMP and increased IP3-> receptor activation leads to inhibiton of PTH secretion
Low Ca concentrations – Increased cAMP and decreased IP3-> no inhibition-> PTH is secreted
Describe the structure of calcium sensing receptor
- Ca receptors on the parathyroid cells
- Seven-transmembrane domain receptor
- Coupled with G-protein complex
- Highly conserved
- 93 % AA homology between human and bovine receptors
- Interaction of receptor with Ca
__ is required for cAMP to decrease
__ is required for IP3 to go up
Gi protein is required for cAMP to decrease
PLC is required for IP3 to go up
Funciton of PLC
Converts IP2 to IP3
PTH effect on the bone
PTH increases the resorption of bone by stimulating osteoclasts and promotes the release of calcium and phosphate into the circulation.
Mineral content of bones
- 99% of total Ca+2
- 90% of total PO4-3
- 50% of total Mg+2
Cell content of bones
- Osteoprogenitor cells
- Osteoblasts
- Osteocytes
- Osteoclasts
Organic matrix content of bones
- Collagen (90-95%)
- Proteoglycans
- Glycoproteins
- Lipids
Name 2 important bone proteins
Osteocalcin and osteonectin
Describe Osteocalcin
Secreted by osteoblasts)
1-2% of bone protein
1mg of osteocalcin binds 17 mg of hydroxyapatite
Serum level is indicator of bone growth.
Describe Osteonectin
Secreted by fibrolasts
Binds collagen and hydroxyapatite
May serve as nucleator for calcium deposition in the bone
forms centres of calcification
Long bones vs trabecular bones
In contrast to the long bones, other parts of the skeleton are more irregular in their structure (trabecular bone)
Process of osteblast differentiation and bone formation
Osteoblast differentiationMesenchymal stem cells (fibroblast-like cells located in the bone marrow)
- Mesenchymal stem cells (fibroblast-like cells located in the bone marrow)
- Osteoprogenitor cells: Attached to bone surface, proliferating
- Osteoblasts
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; Secondary mineralization in 1-2 month
- Entombed osteoblasts differentiate into osteocytes. Formation of a network of metabolically active cells
What do osteoblasts secrete?
can secrete collagen which is the most abundant component of organic matrix
allow for mineralization of the matrix
What is an osteocyte
osteocyte- a bone cell, formed when an osteoblast becomes embedded in the matrix it has secreted.
Compact bone vs woven bone
Compact bone: Adult long bones. Regularly arrayed columns of osteons
Woven bone (trabecular bone): Epiphysis, fractures, juvenile bone, bone disorders. Characterized by a haphazard organization of collagen fibers and is mechanically weak.
What is the hallmark of adult bone?
ossification of epiphysis is the hallmark of an adult bone
Epiphysis vs diaphysis
epiphysis is more disorganized
diaphysis is very organized
Turn over of bones: adults vs kids
Turn-over Ca2+ in bone is 100% per year in infants and 18% in adults
What carries out bone remodelling?
Carried out by bone modeling units: osteoclasts dissolve bone followed by osteoblasts that lay down new bone
What are the Factors regulating bone brekd down/building balance
- Mechanical factors
- Hormonal factors induced by PTH
- Paracrine factors (i.e. IGF-II produced by osteoblasts) may act on neighboring osteoblasts and osteoclasts.
- produced locally and act locally
WHat are the precursors of osteoclasts?
Derived from monocytes (Bone marrow, gives rise to macrophages)
What is the function of oestoclasts?
Degrade bone and release Ca++
How to osteoclasts attach to bones?
Attach to bone via integrins and form tight seal
How to osteoclasts degrade bone?
- Proton pumps (H+ dependent ATPases) move from endosomes to the cell membrane where they pump out H+
- Acid pH (~ 4.0) dissolves hydroxyapaptite; acid proteases break down collagen, allowing to free Ca and release into circulation
- Transcytosis of degradation product and release into the interstitial fluid
What can be measured as an index of bone resorption activity
Pyridinoline (collagen breakdown product) in urine is an index of bone resorption activity.
High in kids, low in adults
Is bone degradation by osteoclasts a fast or a slow responseBone remodeling and its hormonal control
Slow response, not involved in acute regulation of calcium homeostasis
Bone remodeling and its hormonal control
WHat is the effect of calcitonin on bone remodelling?
Has an inhibitory action, with formation of an inactive osteoclast
Effect of PTH and calcitriol on bone remodelling
PTH and calcitriol stimulate osteoblasts to produce osteocalst activating factors
PTH effect on the kidneys
PTH also increases renal reabsorption of Ca from urine and inhibits reabsorption
of phosphate
Describe PTHrP
- Parathyroid Related Protein (PTHrP) similar structure to PTH and can bind to PTH receptor but produced by many tissues in fetus and adult
- required for normal development as a regulator of the proliferation and mineralization of chondrocytes and regulator of placental Ca++ transport
- important for growth-> thus it is secreted by the fetus (this is when the highest levels of calcification occur)
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- important for growth-> thus it is secreted by the fetus (this is when the highest levels of calcification occur)
What type of signlling does PTHrP exhibit? Does it ever change?
usually acts in paracrine fashion but overexpression by tumour cells can produce severe hypercalcemia by activating PTH receptor
if there is a tumour producing PTHrP- it can go into the general circulation and then act upon the whole body
Desribe PTH receptor and it’s ligands and distribution
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
Name and describe 3 Diseases of the bone
- Osteopetrosis: “marble bone”
- Increase in bone density due to defective osteoclasts – bones become more brittle and are prone to fracture
- high calcification, increased caclium deposition
- Osteoporosis:
- Excess osteoclast function-> too much calcium is removed
- Frequent fractures (areas with trabecular bone: distal forearm, vertebral body, hip)
- too little caclium -> weak-> break
- Involutional Osteoporosis
- Loss of bone density with age
Normal vs osteoporotic trabecular bone
Calcium through ageing
with age, Ca levels in circulation decline with age
plus in menopause levels decline even more due to the absence of estrogen
Estrogen effect on osteoclast activity
What are the chnages that occur at menopause?
- Inhibition of cytokines that stimulate the development of osteoclasts
(IL-1, IL-6, TNF)-> decreased Osteoclast activity - Stimulation of the cytokine TGFβ that causes apoptosis of osteoclasts-> decreased osteoclast activity
Menopause→ Estrogen levels decrease→ Osteoclast activity increase
Drawbacks of estrogen therapy (and to some extent estrogen/progestin therapy) to prevent osteoporosis
: Increases myocardial disease and strokes, breast cancer,
describe Hyperparathyroidism
frequrency
Characteristics
Etiology
- PTH is released independently of Ca levels
- Rare disease
- Affects approximately 100,000 patients a year
- Primary hyperparathyroidism occurs in 0.1 to 0.3% of the general population and is more common in women (1:500) than in men (1:2000).
- 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
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Signs and symptoms of primary hyperthyrodism
Stones, bones, groans and psychic moans
Groans: gastrointestinal conditions
- abdominal pain
- constipation
- decreased appetite
- nausea
- peptic ulcer disease
- vomiting
Stones (kidney-related conditions)
- flank pain
- frequent urination
- kidney stones
Moans (psychological conditions)
- confusion
- dementia
- depression
- memory loss
Bones (bone pain and bone-related conditions)
- bone aches and pains
- curving of the spine and loss of height
- fractures
Hypoparathyroidism
Causes, symtomps, treatment
may originate from
- failure to secrete PTH,
- altered responsiveness to PTH, Vit. D deficiency or
- a resistance to Vit. D
problems with PTH may arise from:
- surgery
- familial causes
- autoimmune disorders v idiopathic causes
major clinical symptom is increased neuromuscular excitability (tetany)
treatment: Calcium + Vitamin D
What are the hormones that reducehypercalcaemia
Calcitonin is the Only known hormone that reduces hypercalcaemia
Descrie origins and location of C-cells
C-cells derived from neural-crest cells. Dispersed among follicular cells
Is calcitonin importnat? What is the proof?
May not be physiologically important in humans
- Overproduction of calcitonin (tumors of the parafollicular cells of the thyroid) → no phenotypic consequences
- Thyroidectomy → no phenotypic consequences
Is calcitonin gene important?
gene is important, even though calcitonin might not be
calcitonin gene results in many proteins - calcitonin, CGRP, CGRP-1
CGRP is especially made in the nervous system; speculated to act as a neurotransmitter
CGRP also acts as very potent vasodilator via GPCR receptor
How does CGRP act?
Acts upon CRLR (GPCR receptro) that activates Adenelyl Cyclase-> cAMP
What does vit D deficeincy lead to?
Deficiency leads to bone defects and the disease “rickets”, which causes bone deformations and loss of calcium and phosphate from the bones.
Where was Vit D common? How is food used to solve this problem?
- deficiency used to be common in northern climates
- Vitamin D is now commonly added to milk and butter
How is Vit D formed in our bodies?
How is it tuned into a hormone?
- Vitamin D can be formed in the skin from 7-dehydrocholesterol in a photochemical reaction requiring sunlight.
- Vitamin D is converted in the liver and kidney to a hormone that regulates calcium uptake.
conversion occurs at the level of the liver and kidney
liver: D3 is converted to 25-hydroxyvitamin D2 or 25-hydroxyvitamin D3 (one hydroxyl group)
then it is converted into 1, 25-hydroxyvitamin D2 or D3 in the kidney (2 hydroxyl groups) - > calcitrol
24, 25-hydroxyvitamin vs 1,25-hydroxyvitamin
24, 25-hydroxyvitamin D function remains uncertain
1,25-hydroxyvitamin D form only is capable of signalling
What is Vit D2?
Vitamin D2 is a pharmaceutical product made by irradiating ergosterol (present in some plants). Used in food fortification such as margarine and milk
What does levels of Vit D produced in the skin vary based on?
levels of Vit D produced in the skin varies based on the region and time of the day
requires sunlight with more UV radiation
the closer to the equator-> the more Vit D is produced
Describe Vitamin D metabolism
- Main circulating derivatives are 25-OH- cholecalciferol (made in the liver; 3-30 ng/ml) and calcitriol (made in the kidney; 20-60 pg/ml)
- 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 calcitriol (1,25-(OH)2D3 )
What kind of nuclear receptor is Vit D receptor?
nuclear
What is the cellular impact of Vit D?
Vit D leads to gene expression changes; affects various cell types:
- Increased Osteoblast activity (mineralization)
- Increased Osteoclast activity
- Increased Intestinal Ca2+/PO43-absorbtion
- Increased Renal vitamin D degradation (catabolism)
- DecreasedParathyroid hormone synthesis
Calcitriol mechanim in intestine cells
- Calcitriol promotes active Ca2+ uptake in the intestine by maintaining a Ca2+ gradient
- as Ca enters the enterocyte through transporters, it gets attached to various structural proteins such as myosin and calmodulin which are calcium binding proteins;
- 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
- 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
Vitamin D deficiency causes, consequences and treatment
- inadequate sunlight, nutrition or malabsorption (up to 50-60 % of elderly expecially if institutionalized)
- cause abnormal mineralization of bone and cartilage:
- Rickets (children)
- Osteomalacia (adult form of rickets)
Treatment: Vit D intake
Vit D Toxicity: causes, symptoms and treatment
- Overdose either therapeutically or accidently vDifference in storage, catabolism, absorption among individuals influences level required to be toxic
- 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
- ectopic calcification: calcification of soft tissues
- 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)
