calcium + bones (biochem Flashcards
physiological roles of calcium:
- bone & teeth formation
- muscle contraction
- enzyme co-factor
- essential formal blood clotting
- intra- and extracellular messaging
- stabilisation of membrane potentials
- regulation of cell division, prolifertaion and apoptosis
where is calcium distributed?
99% skeleton
intracellular 1%
extracellular 0.1%
normal calcium range
2.2 - 2.6
how much calcium circulates round body freely (%)?
45%
which plasma proteins does calcium bind to?
albumin (80%)
globulins (20%)
average adult daily calcium requirement
which groups is this higher in?
700mg/ day
older adults, teenagers, lactating/ post menopausal women
which 3 hormones regulate calcium levels?
what is the effect on free serum calcium by each hormone?
PTH
vitamin D (calcitriol)
^^ increase serum Ca2+
calcitonin
decreases free serum Ca2+
calcium homeostasis diagram
which enzyme does PTH affect?
1a-hydroxylase
what reaction dose a1-hydroxylase catalyse
calcidiol to calcitriol
what does calcitriol do
1. in bone
2. intestine
3. kidney
- increases bone turnover (i.e. release of Ca2+)
- increases calcium absorption
- enhances Ca2+ and phosphate reabsorption in kidney
calcitonin role
where is it produced?
decreases serum Ca2+ concentration
c-cells of the thyroid gland
what is the role of fibroblast growth factor 23
^^bone reabsorption of calcium
reduces phosphate reabsorption
parathyroid glands:
- what do they produce
- embryological origin
- blood supply
- PTH
- pharyngeal pouches
- inferior thyroid arteries
which 2 types of cell do parathyroid glands contain?
oxyphil cells
chief cells - these synthesise and secrete PTH
PTH
what kind of hormone?
what receptor does it bind to?
which kind of cells secrete and synthesise PTH?
what is required for sustained release?
peptide hormone - therefore v short half-life
G-coupled protein receptor
chief cells
upregulation of gene expression (this increases gland size)
what initiates release of PTH?
CaSR - calcium sensing receptor
physiological action of PTH in kidney
pg 96
- increases Ca2+ absorbption in distal convuluted tubule (mediated by TRPV5)
- inhibits absorption of PO4 at proximal and distal convuluted tubule -
PTH
1. type of hormone
2. receptor
3. site of synthesis
4. signal for synthesis and/ or secretion
- peptide
- G protein coupled receptor (PTHR1 - parathyroid hormone receptor 1)
- chief cells in parathyroid
- low Ca2+
PTH physiological actions
on bone (1)
in kidney (3)
Bone: ^^ bone resorption
Kidney: ^^ PO4 excretion
Kidney: decreases Ca2+ excretion
Kidney: ^^ vitamin D activation
PTH net effect on calcium homeostasis
^^ Ca2+
decreases PO4 3-
calcitriol (vitamin D)
1. type of hormone
2. receptor
3. site of synthesis
4. signal for synthesis and/ or secretion
- secosteroid
- nucleor receptor (VDR)
Hydroxylated
(activated) in the
proximal convoluted
tubules of the kidney
Extra-renal activation
of vitamin D can also
occur - low Ca2+, low phosphate, PTH
normal vit D level
> 50
supplement if any less
physiolocial actions of calcitriol
bone(2)
GI tract (1)
kidney (1)
Bone: ^^ bone formation and
mineralisation
Bone: ^^ bone remodelling
GI tract: ^^ Ca2+ absorption
Kidney: ^^ Ca2+ and PO4
3–
reabsorption
net effect of calcitriol on Ca2+ homeostasis
^^ serum Ca2+
^^ serum phosphate
caclitonin
1. type of hormone
2. receptor
3. site of synthesis
4. signal for synthesis and/ or secretion
- peptide
- G-protein coupled receptor
- c cells in the thyroid glands
- high Ca2+
calcitonin physiological actions
Kidney: ^^ PO4
3– excretion
Kidney: decreases Ca2+ reabsorption
Bone: inhibits osteoclast
function
calcitonin - net effect on Ca2+ homeostasis
vv serum Ca2+
primary hyperparathyroidism
- what happens
- most common cause
- increased PTH secretion by parathyroid glands
- benign tumour
secondary hyperparathyroidism
- what happens
- common cause
- cx
- low serum calcium stimulates PTH secretion/ production
- CKD
- serum calcium begins to rise causing tertiary hyperparathyroidism
where is calcium reabsorbed?
by which mechanisms?
kidneys
1. proximal tubule (60-70%)
paracellular transport, active and passive
- TALH (20-25%)
passive reabsorption - DCT (5-10%)
active transport - collecting duct (0.5-1%)
active transport
what facilitates calcium absorption from the intestine?
vitamin D
what are the 3 mechanisms of calcium reabsorption from the intestine:
- paracellular transport
(if hypocalcaemic also):
2. active uptake and extrusion
3. endo and exocytosis of Ca2+-CaBp complex
what protein does calcium bind to when it is absorbed
CaBP - calcium binding protein
which receptor is involved in calcium uptake from gut in hypocalcaemia?
where is this present?
TRPV6
luminal surface of intestine
what are the 2 processes of active uptake and extrusion of calcium from the gut?
ATPase
ion exchange with 3 Na+
vitamin D
- name of active form
- what kind of receptor does it bind to?
- calcitriol
- nuclear receptor - therefore has cell membrane and intracellular transport proteins
which enzyme catalyses vitamin D3 –> calidiol in liver
25-hydroxylase
which enzyme coverts calcidiol to calcitriol?
where does this act?
1a-hydroxylase
kidney
what does vitamin D do?
has endocrine and paracrine/ autocrine actions:
- regulates Ca2+ uptake from gut and Ca2+ and PO4 reabsorption/ excretion
- regulates immune system’s response to infection/ inflammation
synthesis of vitamin D
- dietary - D2&D3 (10%)
- sunlight - 7-dehydrocholesterol to D3 (90%)
both converted to calcidiol in liver
then to calcitriol in:
- kidney
- endocrine
- depends on serum vit D
- bone calcium effects - non-renal tissues
- paracrine/ autocrine
- ? independent of serum D3
- immune system
normal vit D
how common is deficiency in UK?
> 50 nmol/L
30-50 = insufficient
<25-30 = deficient
<10 = severe deficiency
<50 requires supplementation
1 in 5
how much vitamin D should be supplemented during pre-conception, pregnancy and lactation?
400 IU/ day
phosphate
what’s its role?
- important for intracellular metabolism (e.g. ATP synthesis)
- needed for phosphorylation
- phospholipids in membrance
what does phosphate balance depend on?
- diet and uptake from gut
- intracellular: extracellular movement
- in and out of bone
- urinary excretion
- actively reabsorbed by PCT
- only place of excretion = kidney
how much calcium does foetus contain?
what are it’s Ca levels vs mum
pg 100
20-30g
relatively hypercalcaemic
To cope with the requirements of the fetus, the
mother has decreased/normal levels of PTH, increased
levels of calcitonin and increased levels of vitamin D
role of bone:
- support/ protection
- movement
- haematopoesis
- mineral homeostasis: buffering Ca2+ and PO4
outside bone name
inside bone name
- cortical
- trabecular
bone composition:
10% water
25% organic - type 1 collagen + NCPs
65% mineral - hydroxyapatite
bone repair
- woven (weak) - rapid osteoid production, collagen haphazard
- lamella (strong) parallel collagen (lamellae - sheets_
woven–> lamellar bone requires bone remodelling
BONE REMODELLING ….
osteoblasts trigger bone remodelling following injury by RANKL
osteoclasts eat up old bone
osteoblasts lay down new bone
what do osteoclasts do?
reabsorb old bone
what do osteoblasts do?
lay down new bone
what do osteoblasts secrete?
what does it do?
RANKL
protein that stimulates osteoclasts
what is secreted once there is adequate osteoclast activity?
(in bone remodelling)
OPG (osteoprotegerin)
binds to RANKL to reduce osteoclast activity
what do osteocytes secrete?
sclerostin
FGF 23
what is the role of sclerostin?
what is it inhibitted by?
stimulates osteoclastic activity
inhibited by mechanical force
what is the role of FGF 23?
stimulates osteoblast activity
bone disorders:
too much/ too little bone
too little bone = osteoporosis
too much bone = osteopetrosis
bone disorders
changes in bone structure:
- mineral defect
- collagen defect
- rapid turnover due to overactive osteoclasts = poor quality woven bone
- osteomalacia/ rickets
- osteogenesis imperfecta
- Paget’s disease
rickets signs:
- bowing on weight bearing
- growth plate elongated & widened
- pigeon chest
- short stature
- misshaped skull
- dental abnormalities
- # s
osteoporosis incidence in >50
1 in 2 female
1 in 5 male
diagnostic criteria for osteoporosis = DEXA score (T score)
what is t score?
what is:
i) normal t score
ii) osteopenic t score
iii) osteoporotic t score
T score - standard deviations vs adult at peak bone density
> -1.0 normal
-1.0 to -1.5 osteopenia
<-2.5 osteopororsis
RF for osteoporosis
low BMD
low body weight
RA
poor nutrition (vit D/ Ca2+ deficiency)
physical inactivity
smoking
alcohol
durgs - steroids, heparin
endocrine disorders that cause low BMD
hypogonadism
hyperparathyroidism
hyperthyroidism
Cushing’s
drug mgt osteoporisis
- bisphosphonates
- SERMs
- PTH (small pulses increase osteoblast activity)
- denosumab
HRT - only if other treaments fail , not licensed for osteoporosis specifically
