MSS: The Skeleton and Metabolism Flashcards
What is involved in the endocrine regulation of bone?
- Parathyroid Hormone - role in calcium metabolism and calcium homeostasis
- Thyroid Hormone - controls rate chondrocytes differentiate in the growth plate. In adults excess thyroid hormone can have an affect on osteoclasts leading to osteoporosis.
- Growth hormone - regulates osteoblast differentiation
- Insulin like growth factor (one) - involved in chondrocyte differentiation and linear growth but also has roles in osteoblast and osteoclast differentiation
- Estrogen - inhibits osteoclast differentiation and activity. When menopause occurs there is a loss of oestrogen, leading to loss of bone mass as it can no
longer inhibit osteoclast differentiation
Where is calcium concentration regulated?
- GI tract - where calcium is absorbed from out diet
- Kidneys - where calcium is excreted from the body
- Bones - where calcium is stored in our bodies (contains 99%)
What is the major hormone that is involved in regulating calcium levels?
Parathyroid hormone (PTH) produced by the parathyroid glands. Acts to increase circulating calcium levels within the body.
How does PTH stimulate resorption?
PTH has a direct affect on osteoblasts and an indirect affect on osteoclasts via the PTH1 receptor found on osteoblasts.
- Stimulates the osteoblasts to produce RANKL and inhibits their production of OPG. Osteoclast activity is increased. This will increase bone resorption, breaking
down the hydroxyapatite crystals, calcium and phosphate into circulation. - PTH also stimulates osteoblast differentiation and activity. Increase bone turnover.
What does synthetic PTH do?
- Drug treatment for various bone disorders.
- Increases osteoblast differentiation and favours bone formation. So it has an anabolic effect (increases bone mass)
- Continuous treatment of PTH quickly results in an increase in osteoclastic bone resorption due to the increase in RANKL and inhibition of OPG. So continuous PTH treatment results in a catabolic effect
- Intermittent PTH treatment is anabolic
- Continuous PTH treatment is catabolic
What effect does PTH have on the kidneys?
- Reduce excretion of calcium by increasing calcium reabsorption.
- Decreases reabsorption of phosphate (more phosphate filtered out kidneys and excreted).
- Increases production of active Vitamin D3.
How is active Vitamin D3 created?
- Pro-hormone form for Vitamin D3 in skin when it is exposed to UV radiation from sunlight
- Converted into 25-hydroxy vitamin D in the liver
- In the kidneys, it is then converted into the active form known as 1,25 dihydroxy vitamin D (active vitamin D3)
What does active vitamin D3 do?
- Acts in GI tract to increase calcium absorption from our diet (absence of active vitamin D3 means very little calcium can be reabsorbed)
- Acts on the parathyroid to inhibit the release of PTH (PTH acts on the kidney to increase the production of active Vitamin D3)
How does calcium homeostasis work?
- Low serum calcium stimulates PTH production in parathyroid glands
- PTH acts to increase serum calcium concentration:
- Increases bone resorption
- Increases calcium reabsorption in kidneys
- Stimulates active vitamin D3 production - increases calcium absorption in gut
- High serum calcium and active vitamin D3 inhibit PTH production
What organs are important to maintain phosphate homeostasis?
GI tract - where phosphate is absorbed from the diet
Kidney - excreted in the urine
Bone - where it is stored.
What are the function of osteocytes?
- Form a mechanosensory network throughout bone that detects damage to bone and signals to osteoblasts and osteocytes
- Connects the bone cells to the vasculature and the circulation. So they communicate with the systemic circulation and when they detect that circulating levels of phosphate are high, they produce a hormone called FGF23.
- So osteocytes communicate with systemic circulation as well as bone cells
- High serum phosphate stimulates FGF23 synthesis in osteocytes
What is FGF23?
- Fibroblast Growth Factor-23
- Discovered in 2000, where activating mutations in FGF23 were identified in patients with autosomal dominant hypophosphatemic rickets (FGF23 mutations caused inappropriate excretion of phosphate from kidneys, leaving low levels of phosphate)
- Acts to increase phosphate excretion in the kidney (however it also interacts with PTH and vitamin D3)
How does FGF23 reduce serum phosphate?
- High serum phosphate stimulates FGF23 production by the osteocytes
- Both PTH and active vitamin D3 can also stimulate the production of FGF23 by osteocytes
FGF23 acts via its receptor FGFR1 in the kidney and the parathyroid.
Kidney - inhibits phosphate reabsorption (more phosphate excreted). Also inhibits production of active vitamin D3 so decreased phosphate absorption in gut.
Parathyroid - it inhibits PTH secretion, preventing PTH-induced release of phosphate from bones
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?
- Osteomalacia in adults
- Rickets in children
- Osteoid is laid down normally by osteoblasts but cant be mineralised into mature bone. Remains as organic portion of bone (soft bone).
Effectively two types:
Vitamin D3 deficiency (causing hypocalcemia) - not enough vitamin D3 produced in skin when exposed to UV radiation, can’t absorb calcium into GI tract so no calcium for bone material
- Phosphate deficiency - no phosphate to be incorporated into calcium hydroxyapatite so bone does not mineralise
Oncogenic Osteomalacia - mesenchymal tumours producing excess FGF23. Excess phosphate excretion, leading to hypophosphatemic rickets.
