MSS: The Skeleton And Metabolism Flashcards
What are the functions of our bones?
- Support and movement: attachment site for muscles
- Protection for internal organs
- provide home for bone marrow
- Acts as mineral reservoir
- Endocrine: Source of some ‘non classical’ hormones
Describe the bone structure
- Cortical (compact) bone
- Trabecular (spongy, cancellous) bone
Describe the composition of the bone
- Protein: Organic osteoid matrix (25%)
- Mineral (75%)
- Cells
Describe the organic osteoid protein matrix in more detail
- Mainly type 1 collagen
- Gives both flexibility and tensile strength
Describe the bone minerals in more detail
- Has a hydroxy apatite
- Calcium and phosphate
- Rigid, brittle: Gives a higher compressive strength
Describe the cells part of the bone composition
Consists of:
- Osteoblasts
- Osteocytes
- Osteoclasts
- Bone marrow cells such as
- Mesenchymal (stromal) stem cells
- Haematopoietic stem cells
How can the bone be seen as a metabolic organ?
Bone turnover serves homeostasis of Serum, Calcium, Phosphates in conjugation with:
- Parathyroid hormone (PTH)
- Vitamin D (1,25 dihydroxy D3)
- FGF-23
What is the daily calcium turnover?
List the Daily intake and Extracellulae plasma conc
- Daily intake recommended: 1000-1200mg (25-30 mmol)
- Extracellular plasma [Ca]:2.2-2.6 mmol L-1
- About half is free [Ca2+] (physiologically active)
- And the other half is protein bound (mainly albumin)
Name some hormones that have skeletal effects
- Oestrogen
- Androgens
- Cortisol
- Parathyroid hormone (PTH)
- Vitamin D (calcitriol)
- Calcitonin
What hormone is secreted from the skeleton?
FGF-23 (Fibroblast growth factor 23)
Where are Parathyroid glands synthesised from?
- Parathyroid hormone (PTH) synthesised by parathyroid chief cells
- Function is to increase Serum [Ca]
- Secreted as 84 AA polypeptide
- Short half life in circulation (<5 min)
What is the function of the parathyroid hormone?
To increase Serum [Ca]
How is the Parathyroid hormone related to Calcium?
- Major hormone in calcium homeostasis
- Plasma Ca is maintained 2.2 - 2.6 mM (total Ca; ionised Ca2+ is approximately half)
- Free (ionised) Ca2+ sensed by GPCR on chief cells
- Ca binding suppresses PTH release
Name one type of Vitamin D
Calcitriol (The most active form)
Where is it synthesised?
Synthesised in the skin in response to exposure to UV (Sunshine vitamin)
How is Calcitriol activated?
Activated by 2 metabolic steps:
- 25 hydroxyl action in liver to form 25 OH D3, major circulating metabolite
- 1â hydroxylation of 25 OH D3 in kidney produces 1,25 (OH)2 D3 or calcitriol, the active hormone
- Needed for Ca absorption of the gut
Where are the Parathyroid hormones regulated?
- Regulated at the chief cells of the PT gland
- Secretion increases as plasma [Ca2+] decreases
What activity does PTH carry out?
- Promotes release of Ca from bone
- Increases renal Ca reabsorption
- Increases renal phosphate excretion
- Upregulates 1α hydroxylase activity
Where is Calcitriol regulated?
- Regulated by the control of 1ã hydroxyl in the kidney
- Increased by: PTH, Low phosphate
What are the actions of Calcitriol?
- Increase absorption of Ca and Pi from GI tract
Little absorption in absence - Inhibits PTH secretion (transcription)
- Complex effects on bone, generally in synergy with PTH
Describe the calcium homeostasis
- 99% of body calcium is in the bones
- Remaining 1% is mainly intracellular
- Hormonal control of the tiny (0.1%)
- Extracellular fraction is what maintains Ca balance
What are the actions of PTH on the bone?
- PTH receptors on osteoblasts and osteocytes
- Activates osteoclasts via RANKL
- Promotes bone remodelling
What are the effects dependent on?
Depends on concentration dynamics
- Intermittent low doses are anabolic (bone formation)
- Persistent high concentration are catabolic (excess resorption over formation – bone loss)
What are osteocytes also known as?
- as Endocrine cells
- Lacunocanalicular network permits communication between osteocytes and from osteocytes to surface cells and systemic circulation
Where does communications take place in the Structure of lacunocanalicular network?
Communications via osteocytes between systemic circulation and bone
Describe the FGF 23 hormone
- secreted by osteocytes
- Hypophosphatemic rickets: rare phosphate-wasting conditions leading to bone mineralization defects (osteomalacia)
- Consortium investigating autosomal-dominant HR (ADHR) traced mutation in gene that turned out to be FGF-23
What is the role of FGF-23?
Has a central role in phosphate homeostasis
What are the actions of FGF-23?
- Expressed and secreted by osteocytes
- Increases renal Pi excretion (by reducing Na-Pi reabsorption from proximal tubule)
- Increased by calcitriol and Pi
- Inhibits calcitriol synthesis
What is Osteoporosis?
A loss of bone mass (Mineral and organic matrix)
What are the causes of osteoporosis?
- Endocrine
- Malignancy
- Drug-induced
- Renal disease
- Nutritional
- Age
What is Osteomalacia?
What are some signs and symptoms?
- Loss of bone mineralisation (termed rickets in children)
Signs and symptoms:
- Permanent deformities in bone growth (rickets)
- Diffuse aches and pains
- Chronic fatigue
- Weak bones
What is Osteomalacia characterised by?
- Low Ca, and / or Pi
- Elevated alkaline phosphatase
- PTH may be elevated
Causes - Vit D deficiency (most common)
- Vit D metabolism defect (rare)
- Phosphate wasting (rare)
State some endocrine causes of osteoporosis
- Hypogonadism – notably any cause of oestrogen deficiency
- Excess glucocorticoids – endogenous or exogenous
- Hyperparathyroidism
- Hyperthyroidism
What is the normal level of Calcium?
- State some Calcium disorders
Normal range 2.2 – 2.6 mM
- Hypocalcaemia
- Hypercalcaemia
State some clinical features of hypercalcemia
- Depression, fatigue, anorexia, nausea, vomiting
- Abdominal pain, constipation
- Renal calcification (kidney stones)
- Bone pain
- Severe: cardiac arrhythmias, cardiac arrest
List the most common causes of hypercalcaemia
- In ambulatory patients: primary hyperparathyroidism
- In hospitalized patients: malignancy
List the least common causes of hypercalcaemia
- Hyperthyroidism
- Excessive intake of vitamin D
What is Primary hyperparathyroidism?
- Usually due to a benign adenoma in one or more PT glands
- Often detected on screening – many patients asymptomatic
-~10% of patients present with clinical evidence of bone disease - 10 - 20% of patients present with kidney stones
- Resolved by surgical removal of affected gland(s)
Describe the Hypercalcaemia of malignancy
- Common problem of advanced malignancy
- Tumour may secrete PTH-related peptide, binds and activates PTH receptor
