MSS: The skeleton and metabolism Flashcards
List some hormones with systemic endocrine interactions with bone.
Hormones with skeletal effects:
- Oestrogen
- Androgens
These are both important for bone formation in both sexes. - Cortisol (promotes bone reabsorption - organic matter of bone contains amino acids so bone reabsorption releases digestive amino acids into circulation to promote gluconeogenesis) –> prolonged high levels of cortisol (e.g. glucocorticoid medication) can lead to loss of bone mass.
- Parathyroid hormone (PTH)
- Vitamin D (calcitriol)
- calcitonin
Hormones secreted from the skeleton:
- FGF-23 (fibroblast growth factor 23)
Describe how the bone acts as metabolic organ and is involved in the homeostasis of calcium.
Bone turnover serves homeostasis of serum calcium, phosphate, in conjunction with
- Parathyroid hormone (PTH) –> increase extracellular Ca2+ levels
- Vitamin D (1,25-dihydroxy D3) –> useful for calcium absorption from the diet
- Calcitonin –> decreases extracellular Ca2+ levels
- FGF-23 –> synthesised and secreted by osteocytes.
In the short term, bone remodelling releases minerals, notably calcium, into the circulation, and therefore can be controlled in the short-term in the service of calcium homeostasis.
Describe the daily calcium turnover.
Daily calcium intake is recommended to be at 1000-1200mg (25-30 mmol).
Extracellular: plasma calcium levels are kept at 2.2-2.6 mmol/L.
About half is free ionised [Ca2+] (physiologically active), and the other half is protein bound (mainly to albumin).
Briefly describe Calcium homeostasis.
About 1000mg of calcium is taken in per day. About 350mg is absorbed in the gut and 150 mg of this used in secretion (digestion) meaning there is a 200mg net gain of calcium. 800mg of calcium will be lost through in feces. This 200mg excess must be removed to keep the extracellular load constant - achieved via the kidney (excreting appropriate amount through urine.) There is ultimately about 900mg of Ca2+ in extracellular fluid which corresponds to the 2.2-2.6mmol L^-1.
Calcium Homeostasis:
- 99% of the body’s calcium is locked in bone mineral - this represents a reservoir. (Bone reabsorption will release calcium into ECF and bone formation will remove it from the ECF - overtime the 2 processes even out). –> PTH acts here.
- Remaining 1% is mainly intracellular (in vesicles).
- Hormonal control of the tiny (<0.1%) extracellular fraction is what maintains Ca balance.
Describe the parathyroid hormone.
PTH is synthesised by parathyroid chief cells, which is secreted as an 84 amino acid polypeptide in response to low levels. It has a short half-life in the circulation of <5 minutes. It exerts its actions via binding to a GPCR in target cells.
PTH is the main hormone that prevents calcium levels from falling too low. It increases the fraction of calcium reabsrobed by the kidney (decrease calcium excretion by urine). PTH also acts to stimulate bone remodelling which cause calcium to be released by the bone mineral into the ECF.
- It has a major role in defence against hypocalcaemia.
- Plasma Ca is maintained at 2.2-2.6mM (free ionised Ca2+ is approximately half)
- Free calcium is sensed by GPCR on chief cells. Calcium binding to them suppresses PTH release.
Small change in Ca2+ can cause a large change in PTH secretion.
In order to maintain calcium homeostasis, PTH is dependant on Vitamin D.
Describe Vitamin D.
It is needed for Ca absorption from the gut.
- It’s a steroid hormone (not really a vitamin) called calcitriol.
- It is synthesised in the skin in response to exposure to UV (‘sunshine vitamin’).
- Can get a bit from diet too (10%.)
How is calcitriol (vitamin D3) produced?
Cholecalciferol is produced from a cholesterol like precursor (7-dehydrocholesterol) in the skin which requires UV light or from diet.
Calcitriol is activated by 2 metabolic steps:
- hydroxylation reaction in the liver: 25 hydroxylation in the liver to form 25 OH D3 (25-hydroxy VitD3), the major circulating metabolite (this is the prohormone).
- then a further 1α hydroxylase enzyme catalyses the conversion of 25 OH D3 in the kidney to produce 1,25 (OH)2 D3, known as calcitriol, the active steroid hormone.
Vitamin D in the circulation is 1,25 (OH)2 D3 (this would be measured in a lab test).
Active Vitamin D is calcitriol.
What are the actions of calcitriol?
Site of regulation of 1α hydroxylase in kidneys.
Increased by:
- PTH
- Low serum phosphate
Actions:
- INCREASE absorption of calcium and phosphate from the GI tract (little absorption in absence)
- inhibits PTH secretion from parathyroid gland (down regulates transcription of precursor gene)
- complex effects on bone, generally in synergy with PTH
It binds to nuclear receptors (as it is a steroid hormone.)
What are the actions of PTH?
Site of regulation of chief cells of PT gland. Secretion increases as plasma [Ca2+] decreases
Actions:
- promotes release of calcium from the bone (via remodeling)
- increases renal calcium reabsorption from kidney
- increases renal phosphate excretion (decrease absorption)
- up-regulates 1α hydroxylase enzyme activity in kidney: –> increases calcitriol –> increases calcium absorption from the gut.
Calcitriol here permits a source of dietary calcium to replenish the pool of extracellular calcium.
What are the actions of PTH on bone?
(since there are PTH receptors on oestoblasts and osteocytes)
- promotes bone formation
- activates osteoclasts via RANKL
- promotes bone remodelling
The effect depends on the concentration dynamics:
- intermittent low doses are anabolic (net building up of bone) –> in some cases this can be used to treat osteoporosis.
- persistent high concentrations of PTH leads to a net loss of bone. It can lead to excess resorption over formation - bone loss (increased calcium in ECF) thus can be damaging and potentially lead to osteoporosis.
Describe calcitonin, its target organs and its effects?
not in lecture slides - from previous years
It is a 32 amino acid peptide.
It’s secreted by the C cells of the thyroid. Its stimulus for secretion is high [Ca2+].
KIDNEY: decreases calcium and phosphate reabsorption
BONE: decreases bone resorption by inhibiting osteoclast activity
Synthetic calcitonin is used in treatment of Paget’s disease of the bone and severe osteoporosis.
What is the purpose of the Lacunar-canalicular network?
It allows for the communication between osteocytes, as well as from osteocytes to surface cells and systemic circulation.
Describe FGF-23 (fibroblast growth factor 23).
FGF-23 is a hormone that is synthesised and secreted from osteocytes, released into the circulation and acts systemically.
Hypophosphatemic rickets is a rare phosphate-wasting (in urine) condition leading to bone mineralisation defects such as osteomalacia.
Consortium investigating autosomal-dominant hypophosphatemic rickets (ADHR) traced a mutation in a gene that turned out to be FGF-23.
When the peptide is into the circulation it is normally degraded via enzymatic cleavage, however, in the case of this mutation (to the cleaving site - FGF-23 is no longer recognised) the peptide isn’t cleaved and is thus persistently active. Therefore too much FGF-23 results in the loss of too much phosphate.
Thus, we know it has a central role in phosphate homeostasis.
It was discovered in 2000.
What are the actions of FGF-23?
Example of bone acting as an endocrine organ
- It increases renal phosphate excretion (by reducing Na-Pi reabsorption (by down regulating activity of Na-Pi cotransporter) from the proximal tubule)
- It is expressed and secreted by osteocytes
- increased by calcitriol and phosphate
- inhibits calcitriol synthesis
Rises in phosphate stimulates increased release of FGF-23 from osteocyte (NF loop) –> increases phosphate excretion therefore countering the rise. - important.
Calcitriol release is increased by low phosphate levels. FGF-23 down regulates production of calcitriol, whereas if calcitriol production increases, this upregulates the production of FGF-23 and this will upregulate phosphate excretion. There are also additional PTH interactions.
See diagram.
Briefly, describe disorder of Calcium.
- Normal range 2.2mM
- Hypocalcaemia (below 2.2mM)
- Hypercalcaemia (above 2.6mM)
Both are common in hospitalised patients.
