The Skeleton and Metabolism Flashcards
What are the categorical functions of bone?
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
How is bone regulated endocrinologically?
Parathyroid Hormone
Thyroid Hormone- controls the rate at which chondrocytes differentiate to the growth plate
Growth hormone- regulates osteoblast differentiation
Insulin like growth factor- involved in chondrocyte differentiation
Oestrogen- inhibits osteoclast differentiation and activity
What three tissues are involved in calcium metabolism?
It is necessary to maintain circulating calcium in a small homeostatic range
This is done via calcium metabolism involving three tissues:
The GI tract where calcium is absorbed through our diet
The kidneys where calcium is excreted
The bones where calcium is stored
How does each of the three tissues regulate calcium metabolism?
Gastrointestinal tract - Calcium intake ~1g/day - Around 30% is absorbed Kidney - Calcium excretion in urine - Moderated by reabsorption Bone - Reservoir to maintain homeostasis
What are the parathyroid glands?
The major hormone that is important when it comes to regulating calcium levels is produced by the parathyroid gland called parathyroid hormone
This is what acts to increase calcium levels in the circulation
How is PTH release stimulated?
Low calcium stimulates PTH release
When calcium levels fall below the homeostatic range this is detected in the parathyroid glands, stimulating the release of PTH
PTH’s effect on the bone cells is to increase bone resorption, breaking down some of our bone and releasing the calcium and phosphate stored into our circulatory system
How does PTH stimulate resorption via RANKL/OPG?
PTH has a direct effect on osteoblasts and an indirect effect on osteoclasts
Via the PTH1 receptor on osteoblasts, PTH has several effect, the important one being that it stimulates the production of RANKL and inhibits the production of OPG
BY increasing the amount of RNKL and inhibiting OPG you have altered the paracrine ratio and so increase osteoclast activity and differentiation which will then increase and break down those hydroxybutyrate crystals releasing calcium and phosphate
PTH also stimulates osteoblast differentiation.
- Intermittent PTH treatment is anabolic
- Continuous PTH treatment is catabolic and lose bone mass
What are the PTH actions on the kidney?
PTH also has an effect on the kidneys
It acts on the kidneys to reduce the excretion of calcium from the kidneys by increasing calcium reabsorption
It also increases the amount of phosphate excreted by the kidneys by decreasing the reabsorption of phosphate
It also increases the production of active vitamin D3 which is actually a hormone produced by the kidneys
How is active vitamin D3 produced?
We make most of the prohormone form for vitamin D3 in our skin when it is exposed to UV radiation form sunlight
This is then converted to 25 hydroxy vitamin D3 in the liver and then in the kidneys can be converted to 1,25 dihydroxy vitamin D3 or active vitamin D3
This active vitamin D3 has two key effects:
- It acts in the GI tract to increase calcium absorption form our diets
- Goes to the parathyroid and acts there to inhibit the release or PTH
High calcium & D3 inhibit PTH production
So PTH indirectly increases calcium absorption in the gut
What three tissues are involved in phosphate metabolism?
Without phosphate and calcium you cannot have mineralised bone
You can see that the same three organs are involved in the homeostasis of phosphate levels
The GI tracts where it is absorbed, the kidney where it is excreted and the bone where it is stored
How are osteocytes endocrine cells?
Osteocytes communicate with systemic circulation as well as bone cells
High serum phosphate stimulates FGF23 synthesis in osteocytes
What is FGF23 and its role?
Fibroblast Growth Factor-23
In 2000, activating mutations in FGF23 were identified in patients with autosomal dominant hypophosphatemic rickets
Acts to increase phosphate excretion in the kidney.
Interacts using two other hormones, PTH and vitamin D3
How does FGF23 act to reduce serum phosphate?
PTH as mentioned causes bone resorption which also releases phosphate
This high phosphate serum levels will stimulate FGF23 production by the osteocytes
PTH and active D3 can stimulate the production of FGF23 by osteocytes
FGF23 acts via its receptor FGFR1 acting in two key places:
- In the kidney where it inhibits phosphate reabsorption and inhibits the production of active vitamin D3 to decrease phosphate absorption in the gut
- FGF23 also acts on the parathyroid to inhibit PTH synthesis and PTH secretion
What is a 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?
Rickets(in children) / Osteomalacia (in adults)
Defective mineralisation of normally synthesized bone matrix
Rickets in children
Effectively two types:
- Deficiency of vitamin D3 (causing hypocalcemia) so cannot absorb calcium
- Deficiency of Phosphate
Oncogenic Osteomalacia
- mesenchymal tumours producing excess FGF23 leading to hypophosphatemic rickets
