MSS: The Skeleton and Metabolism Flashcards
List some hormones with skeletal effects.
- oestrogen
- androgens
- cortisol
- parathyroid hormone (PTH)
- Vitamin D (calcitriol)
- calcitonin
Describe the daily calcium turnover.
Daily calcium intake is recommended to be at 1000-1200mg (25-30 mmol).
Extracellular calcium levels are kept at 2.2-2.6 mmol/L.
About half is free [Ca2+] (physiologically active), and the other half is protein bound (mainly to albumin).
What is the role of bone as a metabolic organ?
Bone turnover serves the homeostasis of serum calcium and phosphate, in conjunction with:
- parathyroid hormone (PTH)
- Vitamin D (1,25-dihydroxy D3)
- Calcitonin
- FGF-23
Describe the parathyroid hormone.
PTH is synthesised by parathyroid chief cells, which is secreted as an 84 amino acid polypeptide. It has a short half-life in the circulation of <5 minutes.
It has a major role in defence against hypocalcaemia.
Free calcium is sensed by GPCR on chief cells. Calcium binding to them suppresses PTH release.
Describe Vitamin D.
It’s not actually a vitamin; it’s a steroid hormone called calcitriol.
It is synthesised in the skin in response to exposure to UV (‘sunshine vitamin’).
How is cholecalciferol activated to calcitriol?
It is activated by 2 metabolic steps:
- 25 hydroxylation in the liver to form 25 OH DW, the major circulating metabolite
- then a further 1α hydroxylation of 25 OH D3 on the kidney produces 1,25 (OH)2 D3, or calcitriol, the active hormone
Thus, the site of regulation is control of 1α hydroxylase in the kidney. It is increased by:
- PTH
- low phosphate levels
What are the actions of calcitriol?
- increase absorption of calcium and phosphate from the GI tract
- inhibits PTH secretion (transcription)
- complex effects on bone, generally in synergy with PTH
What are the actions of PTH?
- promotes release of calcium from the bone
- increases renal calcium reabsorption
- increases renal phosphate secretion
- up-regulates 1α hydroxylase activity
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
- persistent high concentration leads to excess resorption over formation - bone loss
Describe calcitonin.
It is a 32 amino acid peptide.
It’s secreted by the C cells of the thyroid. Its stimulus for secretion is high [Ca2+].
What are the target organs for calcitonin, and what are its effects?
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 and from osteocytes to surface cells and systemic circulation.
Describe FGF-23 (fibroblast growth factor 23).
It was discovered in 2000.
Hypophosphatemic rickets is a rare phosphate-wasting condition leading to bone mineralisation effects (osteomalacia). Consortium investigating autosomal-dominant hypophosphatemic rickets (ADHR) traced a mutation in a gene that turned out to be FGF-23.
Thus, we know it has a central role in phosphate homeostasis.
What are the actions of FGF-23?
- expressed and secreted by osteocytes
- increased by calcitriol and phosphate
- inhibits calcitriol synthesis
- increases renal phosphate excretion (by reducing Na-Pi reabsorption from the proximal tubule)
What are the clinical features of hypercalcaemia?
- depression, fatigue, anorexia, nausea, vomiting
- abdominal pain, constipation
- renal calcification (kidney stones)
- bone pain
Severe:
- cardiac arrhythmias, cardiac arrest
