MSS: The Skeleton & Metabolism Flashcards by aimen n

Name hormones that induce effects on the skeleton

Oestrogen 
Androgens 
Cortisol 
Parathyroid hormone (PTH)
Vitamin D (calcitriol)
Calcitonin

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What hormone is secreted from the skeleton?

FGF-23 (fibroblast growth factor 23)

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What is the daily recommended calcium intake?

Daily intake recommended :

1000-1200mg (25-30 mmol)

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What is the normal extracellular [Ca2+]?

Extracellular: plasma Ca 2.2-2.6 mmol L-1

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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

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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

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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

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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

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Where is parathyroid hormone produced?

PTH synthesised by parathyroid chief cells

Secreted as 84 AA polypeptide

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Describe the half life of PTH in circulation

Short half-life in circulation (<5 min)

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How do parathyroid chief cells regulate PTH secretion?

Parathyriod. 80K cells continuously monitoring blood Ca, and increasing or decreasing PTH secretion accordingly

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What is the role of Parathyroid hormone?

Major role is defence against hypocalcaemia

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What is the normal Ca plasma range?

Plasma Ca is maintained 2.2 – 2.6 mM (free, ionized Ca2+ is approximately half)

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How do chief cells suppress PTH release?

Free Ca sensed by GPCR on chief cells

Ca binding suppresses PTH release

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What is vitamin D?

Calcitriol (really a steroid hormone, not a vitamin!)

Synthesised in skin in response to exposure to UV (‘sunshine vitamin’)

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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.

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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

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How are the actions of calcitriol (Vit.D) regulated?

Site of regulation is control of 1α hydroxylase in kidney

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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