W6 -The skeleton and metabolism Flashcards
What are the functions of bone?
- STRUCTURE
– give structure and shape to the body - MECHANICAL
– sites for muscle attachment - PROTECTIVE
– vital organs and bone marrow - METABOLIC
– reserve of calcium and other minerals
What is bone?
INORGANIC - 65%
– calcium hydroxyapatite (Ca10(PO4)6(OH)2)
– is storehouse for 99% of Calcium in the body
– 85% of the Phosphorus, 65% Sodium,
Magnesium
* ORGANIC - 35%
– bone cells and protein matrix
What are the endocrine regulation of bone?
- Parathyroid Hormone - role in calcium metabolism
- Thyroid Hormone - controls the rates at which chondrocytes differentiate in the growth plates and in its absence. In adults, loss can lead to osteoporosis.
- Growth hormone - regulates osteoblast differentiation.
- Insulin like growth factor - also involved in chondrocytes differentiation and linear growth. Also roles in. osteoblasts and osteoclast differentiation.
- Estrogen - inhibits bone remodelling by inhibiting osteoclast differentiation and activity as well as through direct effects on other bone subtypes. Menopause - loss of bone mass.
How does calcium metabolism work?
Without = muscles, nerves, kidneys etc would not function correctly.
Too much = interferes with cardiac, brain functions and painful kidney stones.
GI tract - calcium is absorbed from our diets
Kidneys - calcium is excreted from bodies
Bones - where it is stored in the body
What systems are involved in calcium metabolism?
- Gastrointestinal tract
– Calcium intake ~1g/day - Kidney
– Calcium excretion in urine
– Moderated by reabsorbtion - Bone
– Reservoir to maintain homeostasis - contains 99% of calcium in the body.
What happens at the parathyroid glands?
Parathyroid hormone increases Ca levels in the body. These act to increase circulating hormone levels.
What does low calcium stimulate?
Low serum calcium (circulating calcium) detected by the parathyroid glands stimulating the release of PTH.
One of the actions is to increase bone resorption. Breaking down some of the bone and releasing the calcium and phosphate stored within that bone into the circulation system.
How does the PTH stimulate resorption via RANKL/OPG
- PTH also stimulates osteoblast differentiation.
– Intermittent PTH treatment is anabolic
– Continuous PTH treatment is catabolic
Direct effect on osteoblasts and an indirect effect on osteoclasts via the PTH1 Receptor found on osteoblasts. It stimulates osteoblasts to produce RANK ligand. By increasing RANKL and inhibiting OPG, we alter the paracrine ratio in favour of increasing the amount of available RANKL.
The PTH also has an effect on bone turnover. The frequency at which the bone remodelling cycle occurs.
Synthetic PTA has been produced and used as a drug treatment for various bone disorders. Normally called PTH 1-34 and consists of the first 34 amino acids of PTH. When it’s given, the initial effect is on the osteoclast differentiation and changing the balance within the bone remodelling cycle to favour bone formation. (Anabolic effect, increasing the bone mass).
Continuous PTH treatment quickly results in the effect in osteoclast bone resorption due to the increased RANKL and inhibition of OPG (catabolic effect - net loss of bone mass).
What are the PTH actions in the kidney?
It acts on the kidneys to reduce the excretion of calcium from the kidneys by increasing calcium reabsorption. Amounts of calcium in the bloodstream is increased by preventing excretion. Also increases the amount of Phosphate excreted by the kidneys by decreasing the reabsorption phosphates - more phosphate is filters out to the kidneys and excreted.
It also increases the production of active vitamin D3 - this is a hormone produced by kidneys. We make most of the pro hormone form for vitamin D3 in our skin when it is exposed to UV radiation from sunlight. This is then converted to 25-hydroxy vitamin D3 in the liver and then in the kidneys converted to the active form of: 1,25 dihydroxy vitamin D3. This then has 2 effects.
1) Acts on the GI tract to increase calcium absorption from our diets.
2) Goes to parathyroid and acts there to inhibit the release of PTH.
All of this acts to increase the serum calcium levels in the blood, closing the feedback loop.
What is Phosphate metabolism?
Less than 1% is in circulation.
GI tract - phosphate is absorbed from diet
Kidney - it is excreted in the urine
Bone - where it is stored
When everything is in balance, the amount of phosphate excreted each day is the same as taken in through the diet.
The hormone to regulate phosphate is made in the bone itself.
What are osteocytes in endocrine cells?
- Embedded in lacunae in mature bone
- Connected via processes through canalicular channels
- Form a mechanosensory network throughout bone, which is able to sense damage.
- Osteocytes communicate with systemic circulation as well as bone cells
- High serum phosphate stimulates FGF23 synthesis in osteocytes
The canalicular network also connects bone cells to vasculature and circulation. Osteocytes have another function - when they detect the circulating phosphate levels are high, they produce the hormone: FGF23
Osteocytes are endocrine cells and the bones are endocrine organs.
What is FGF23?
- Fibroblast Growth Factor-23
- In 2000, activating mutations in FGF23 were identified in patients with autosomal dominant hypophosphatemic rickets. They found out that activating mutations in the FGF 23 were the cause of the condition. It is a phosphate wasting condition, where they cannot maintain a suitable phosphate level in their circulation. It was causing them to consistently inappropriately excrete any phosphate they had via their kidneys.
- Acts to increase phosphate excretion in the kidney.
They found out that FGF 23 interacts with PTH and Vitamin D3 (involved in calcium metabolism). PTH causes bone resorption, this doesn’t just release calcium from the bone. It also released phosphates increasing serum phosphate concentrations. The high serum phosphate levels will stimulate FGF 23 production by the osteocytes. Both PTH and active D3 can also stimulate production of FGF 23 by osteocytes. FGF 23 acts via its receptor FGFR1 and it acts in two key places.
1) Kidneys: Inhibits phosphate reabsorption so the kidneys are reabsorbing less phosphate. More phosphate is excreted. The kidney also inhibits the production of active vitamin D3. It does this because d3 acts in the GI tract to increase calcium absorption. It also increases phosphate absorption in the GI.
2) Also acts on the parathyroid to prevent PTH secretion, preventing any further PTH induced release of phosphate from the bones.
What is metabolic bone disease?
- A group of diseases that cause reduced bone mass and reduced bone strength
- Due to imbalance of various chemicals in the body (vitamins, hormones, minerals, etc)
- Cause altered bone cell activity, rate of mineralisation, or changes in bone structure
- Osteoporosis is a metabolic bone disease
What is Rickets/Osteomalacia?
Malacia = soft
So, soft bones.
* Defective mineralisation of normally synthesized bone matrix
* Rickets in children
* Effectively two types
– Deficiency of vitamin D3 (causing hypocalcemia) Without exposure to UV radiation means cannot absorb calcium in GI tract.
– Deficiency of Phosphate
* Oncogenic Osteomalacia
– mesenchymal tumours producing excess FGF23
This is a disease where osteoids are laid down normally by osteoblasts, but that osteoid cannot be mineralised into mature bone. It remains as only the organic portion of bone.
In adults = osteomalacia
In children = rickets
What happens to the bone in Osteomalacia?
Normal bone:
Green – mature mineralised bone - most
Orange – unmineralised osteoid - little
Osteomalacia:
Green – mature mineralised bone – very little
Orange – unmineralised osteoid - most
