MSS: The Skeleton & Metabolism Flashcards
Name hormones that induce effects on the skeleton
Oestrogen Androgens Cortisol Parathyroid hormone (PTH) Vitamin D (calcitriol) Calcitonin
What hormone is secreted from the skeleton?
FGF-23 (fibroblast growth factor 23)
What is the daily recommended calcium intake?
Daily intake recommended :
1000-1200mg (25-30 mmol)
What is the normal extracellular [Ca2+]?
Extracellular: plasma Ca 2.2-2.6 mmol L-1
How much of the plasma Ca2+ is bound to proteins?
About half is free [Ca2+] (physiologically active), half protein bound (mainly albumin)
AW Ca = 40, 40 mg = 1 mmol. 900/40 = 22.5 mmol in ECF
What is the significance of Ca2+ levels in the body?
Calcium is not just responsible for our bone strength, but it is the source of electrical energy in our nervous system and muscles
Why is bone such a vital metabolic organ?
Bone turnover serves homeostasis of serum calcium, phosphate, in conjunction with
- Parathyroid hormone (PTH)
- Vitamin D (1,25-dihydroxy D3)
- Calcitonin
- FGF-23
How does bone metabolism aid homeostasis?
Bone remodelling releases minerals, notably calcium, into the circulation, and therefore can be controlled in the short-term in the service of calcium homeostasis
Where is parathyroid hormone produced?
PTH synthesised by parathyroid chief cells
Secreted as 84 AA polypeptide
Describe the half life of PTH in circulation
Short half-life in circulation (<5 min)
How do parathyroid chief cells regulate PTH secretion?
Parathyriod. 80K cells continuously monitoring blood Ca, and increasing or decreasing PTH secretion accordingly
What is the role of Parathyroid hormone?
Major role is defence against hypocalcaemia
What is the normal Ca plasma range?
Plasma Ca is maintained 2.2 – 2.6 mM (free, ionized Ca2+ is approximately half)
How do chief cells suppress PTH release?
Free Ca sensed by GPCR on chief cells
Ca binding suppresses PTH release
What is vitamin D?
Calcitriol (really a steroid hormone, not a vitamin!)
Synthesised in skin in response to exposure to UV (‘sunshine vitamin’)
What is the role of Vitamin D?
Binds to its nuclear receptor, (VDR) typical steroid DNA binding element, etc
Dimerizes with RX receptor. Effects mainly increasing (sometimes decreasing) transcription of target genes.
What activates Vitamin D?
Activated by 2 metabolic steps:
- 25 hydroxylation in liver to form 25OH D3, major
circulating metabolite
- 1α hydroxylation of 25 OH D3 in kidney produces
1,25(OH)2 D3, or calcitriol, the active hormone
How are the actions of calcitriol (Vit.D) regulated?
Site of regulation is control of 1α hydroxylase in kidney
How are effects of Vit. D increased?
Increase absorption of Ca and Pi from GI tract, increased by
- PTH
- Low phosphate
What effect does absence of PTH and high phosphate have on Vit. D effects?
Little absorption in absence
- Inhibits PTH secretion (transcription)
- Complex effects on bone, generally in synergy with PTH
How is the body’s Ca reservoir increased?
The only way to increase the body’s Ca reservoir is via absorption from the gut, and little takes place in the absence of vitamin D.
What are the actions of PTH?
Promotes release of Ca from bone
Increases renal Ca reabsorption
Increases renal Pi excretion
Upregulates 1α hydroxylase activity
Where is majority of the body’s Ca?
99% of body calcium is in bone
Remaining 1% is mainly intracellular
What maintains Ca2+ homeostasis?
Hormonal control of the tiny (<0.1%) extracellular fraction is what maintains Ca balance
What are the effects of PTH on bone?
- PTH receptors on osteoblasts and osteoclasts
- Promotes bone formation
- Activates osteoclasts via RANKL
- Promotes bone remodelling
How does the [PTH] affect its effects?
Effect depends on concentration dynamics
- Intermittent low doses are anabolic
- Persistent high concentration leads to excess resorption
over formation – bone loss
Describe the structure of calcitonin
32 amino acid peptide
Where is calcitonin secreted from?
Secreted by C cells of the thyroid
What stimulates calcitonin secretion?
Stimulus for secretion is high [Ca2+]
What organs does calcitonin produce effects upon?
Kidney
- decreases calcium and phosphate reabsorption
Bone
- decreases bone resorption by inhibiting osteoclast
activity
Synthetic calcitonin used in treatment of Paget’s disease of bone and severe osteoporosis
What is the lacuno-canalicular network?
The osteocyte lacuno-canalicular system (OLCS) is a large network intercommunicating the lacunae and canaliculi which contain the osteocytes and their cytoplasmic processes within the mineralized bone matrix
The vitality and functioning of the osteocytes and cytoplasmic processes depend upon this intercommunication
Whar is the role of the lacuno-canalicular?
Communication, via osteocytes, between systemic circulation and bone
Allows communication between osteocytes and from osteocytes to surface cells and systemic circulation
What is the consequence of FGF-23 gene mutation?
Consortium investigating autosomal-dominant HR (ADHR) traced mutation in FGF-23 gene
Causes hypophosphatemic rickets - rare phosphate-wasting conditions leading to bone mineralization defects (osteomalacia)
What is the significance of FGF-23 gene?
Central role in phosphate homeostasis
Inhibits calcitriol synthesis
Increases renal Pi excretion (by reducing Na-Pi reabsorption from proximal tubule)
Where is FGF-23 secreted from?
Expressed and secreted by osteocytes
What increases FGF-23 secretion?
Increased by calcitriol and Pi
What are common calcium disorders?
Normal range 2.2 – 2.6 mM
Hypocalcaemia
Hypercalcaemia
What are the Clinical Features of Hypercalcemia?
Depression, fatigue, anorexia, nausea, vomiting,
Abdominal pain, constipation
Renal calcification (kidney stones)
Bone pain
“painful bones, renal stones, abdominal groans, and psychic moans,”
Severe: cardiac arrhythmias, cardiac arrest
What are the more common causes of hypercalcaemia?
Most common causes:
In ambulatory patients: primary hyperparathyroidism
In hospitalized patients: malignancy
What are the less common causes of hypercalcaemia?
Less common causes include:
Hyperthyroidism
Excessive intake of vitamin D
What causes hyperparathyroidism?
Usually due to a benign adenoma in one or more PT glands
How is hyperparathyroidism detected?
Often detected on screening – many patients asymptomatic
What do hyperparathyroid patients normally present with?
~10% of patients present with clinical evidence of bone disease
10 - 20% of patients present with kidney stones
How is hyperparathyroidism resolved?
Resolved by surgical removal of affected gland(s)
What is hypercalcaemia of malignancy?
Common problem of advanced malignancy
Tumour may secrete PTH-related peptide, binds and activates PTH receptor
